Compositions and methods for treating hyperprocalcitonemia

Abstract

A composition for treating hyperprocalcitonemia is described, which comprises a lipid-soluble or hydrophobic component, an amphiphilic emulsifier, and a polar liquid carrier, with or without one or more electrolytes, and the amphiphilic emulsifier forms micelles and / or liposomes structured as lipid bilayers and / or other specific configurations having a lipid-soluble or hydrophobic core containing the lipid-soluble or hydrophobic component in the polar liquid carrier.

Description

[Technical Field]

[0001] This application claims priority to U.S. Provisional Patent Application No. 63 / 482,540, filed January 31, 2023.

[0002] FIELD OF THE INVENTION This application relates generally to pharmaceutical compositions and in particular to compositions for treating hyperprocalcitonemia. [Background technology]

[0003] Procalcitonin is a 116-amino acid peptide with an approximate molecular weight of 13.0 kDa. It is expressed in parafollicular cells of the thyroid gland and is enzymatically cleaved to produce the calcium-regulating hormone calcitonin. Normally, procalcitonin production is restricted to these cells, and its concentration in the bloodstream is very low at <0.05 ng / ml. Under conditions of significant physiological stress, monocytes and parenchymal cells of many organs, including adipose tissue, liver, lung, muscle, stomach, kidney, and brain, can synthesize procalcitonin, resulting in a 100,000-fold increase in blood levels. The enzyme converting procalcitonin to calcitonin is absent in tissues other than the thyroid gland. As a result, procalcitonin is released into the bloodstream instead of calcitonin during physiological stress. Recent studies have revealed that procalcitonin is more than just a marker of the inflammatory response; it is also a mediator of this response and, therefore, a target for the treatment of diseases in which its concentration is elevated.

[0004] The inflammatory response is the pathophysiological basis of a wide range of medical conditions, which may or may not involve infection. Examples include bacterial or viral infection, malaria, blood loss, severe heart failure, injury to the brain and / or spinal cord, fractures, non-orthopedic trauma, pancreatitis, burns, ischemic stroke, subarachnoid hemorrhage, heat stroke, vasculitis, metastatic cancer, dementia, sarcopenia, aging, chronic or acute kidney disease, chronic or acute liver failure, heart failure, acute respiratory distress syndrome, and arthritis. In vitro and in vivo studies have revealed a role for procalcitonin as a mediator of inflammation and tissue injury, which are characteristic of many of these medical conditions.

[0005] Procalcitonin, like the pro-inflammatory cytokine interleukin-8, has been shown to increase intracellular calcium levels (Becker et al. Procalcitonin in sepsis and systemic inflammation: a harmful biomarker and a therapeutic target. Br. J. Pharmacol. 2010 159(2):253-264).

[0006] Studies using rat aortic vascular smooth muscle cells showed that procalcitonin did not directly affect nitric oxide release from these cells. However, when combined with lipopolysaccharide, tumor necrosis factor, and interferon-γ, procalcitonin significantly increased nitric oxide production from these cells (Tilg, Peschel, Interferon-alpha and its effects on the cytokine cascade: a pro- and anti-inflammatory cytokine. Leuk. Lymphoma 1996 23(1-2):55-60). Thus, procalcitonin is not a primary inducer but an amplifier of the inflammatory response. Furthermore, procalcitonin has direct effects that make it a toxic mediator.

[0007] Examples of procalcitonin as a toxicity mediator are abundant in the literature. Wagner et al. (Procalcitonin Impairs Endothelial Cell Function and Viablity. 2017;124(3):835-845) demonstrated that procalcitonin induces endothelial barrier disruption, cell migration, new capillary formation, and endothelial cell death. Furthermore, recovery of hindlimb perfusion in ischemic limbs was impaired in mice. Sauer et al. (Procalcitonin Impairs Liver Cell Viability and Function In Vitro: A Potentially New Mechanism of Liver Dysfunction and Failure during Sepsis? Biomed Research International Volume 2017:Article 6130725 Open Access) found that procalcitonin inhibits hepatocyte proliferation and induces hepatocyte death. Using procalcitonin-deficient mice, the role of procalcitonin as a toxicity mediator was further elucidated. These mice were protected from septic shock and showed reduced lung inflammation (Baranowsky et al. Procalcitonin Exerts a Mediator Role in Septic Shock Through the Calcitonin Gene-Related Peptide Receptor. Crit. Care Med. 2021 49(e41-e52)). Sullivan and Schmidt demonstrated procalcitonin-induced microcirculatory dysfunction (Procalcitonin: A Mediator of Microvascular Dysfunction during Critical Illness. American Journal of Respiratory and Critical Care Medicine 2022 206(4):375-376).Infusion of procalcitonin into septic animals increased mortality, while administration of procalcitonin antibodies reduced mortality in septic animals (Becker et al. Procalcitonin in sepsis and systemic inflammation: a harmful biomarker and a therapeutic target. Br. J. Pharmacol. 2010 159(2):253-264).

[0008] In humans, lower blood procalcitonin has been shown to indicate a favorable prognosis in many conditions, such as sepsis, acute respiratory distress syndrome, fractures, acute kidney injury, heart failure, and trauma. Given its action as an amplifier of the inflammatory response and the direct adverse effects of procalcitonin, agents that lower procalcitonin would be beneficial in acute or chronic conditions in which procalcitonin is elevated. Summary of the Invention

[0009] One aspect of the present application is a method for treating hyperprocalcitonemia in a subject in need thereof, comprising administering to the subject in need thereof an effective amount of a nanoparticle composition comprising: an amphiphilic emulsifier in an amount of 0.1% to 100% (w / v); a lipophilic or hydrophobic component in an amount of 0 to 35% (w / v); a polar liquid carrier; and one or more electrolytes, wherein the nanoparticle composition comprises liposomes and / or micelles having an average diameter of 1 to 800 nm.

[0010] Another aspect of the present application relates to a method for treating a disease or condition associated with elevated procalcitonin in a subject, including, but not limited to, chronic or acute renal failure, chronic or acute liver failure, chronic or acute respiratory failure, age-related sarcopenia, dementia, orthopedic or non-orthopedic trauma, surgical procedures, myocardial infarction, autism, ischemic stroke, Parkinson's disease, vasculitis, bone fractures, blood loss, and depression. The method comprises administering to a subject in need of treatment for hyperprocalcitonemia an effective amount of a hydrophobic nanoparticle composition comprising: an amphiphilic emulsifier in an amount of 0.1% to 100% (w / v); a lipid-soluble or hydrophobic component in an amount of 0 to 35% (w / v); a polar liquid carrier; and one or more electrolytes, wherein the nanoparticle composition comprises liposomes and / or micelles having a diameter in the range of 1 to 800 nm.

[0011] Another aspect of the present application relates to a method for treating aging, comprising administering to a subject in need thereof an effective amount of a nanoparticle composition comprising: an amphiphilic emulsifier in an amount of 0.1% to 100% (w / v); a lipophilic or hydrophobic component in an amount of 0 to 35% (w / v); a polar liquid carrier; and one or more electrolytes, wherein the nanoparticle composition comprises liposomes and / or micelles having a diameter in the range of 1 to 800 nm. DETAILED DESCRIPTION OF THE INVENTION

[0012] Reference will now be made in detail to certain aspects and exemplary embodiments of the present application, examples of which are illustrated in the accompanying structures and drawings. Aspects of the present application will be described in conjunction with representative embodiments, including methods, materials, and examples; such descriptions are non-limiting, and the scope of the present application is intended to encompass all equivalents, alternatives, and modifications, whether generally known or incorporated herein. Unless otherwise specified, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which the present application belongs. Those skilled in the art will recognize many techniques and materials similar or equivalent to those described herein, which can be used in the practice of the aspects and embodiments of the present application. The described aspects and embodiments of the present application are not limited to the methods and materials described.

[0013] As used in this application and the appended claims, the singular forms "a," "an," and "the" include plural references unless the context clearly dictates otherwise.

[0014] Ranges may be expressed herein as from "about" one particular value, and / or to "about" another particular value. When such a range is expressed, another embodiment includes from the one particular value and / or to the other particular value. Similarly, when values ​​are expressed as approximations, it is understood that the particular value forms another embodiment by the use of "about." It is further understood that the endpoints of each of the ranges are significant both in relation to the other endpoint, and independently of the other endpoint. It is understood that there are a number of values ​​disclosed herein, and that each value is also disclosed herein as "about" that particular value in addition to the value itself. For example, if a value of "10" is disclosed, then "about 10" is also disclosed. When a value is disclosed as "less than or equal to, greater than or equal to," it is understood that the possible range between the values, as approximately understood by one of ordinary skill in the art, is also disclosed. For example, if the value "10" is disclosed, then "less than or equal to 10," as well as "greater than or equal to 10," is also disclosed.

[0015] I. Definition The term "acute critical illness" is intended to include any condition that places a patient in urgent need of intensive care. This condition may be caused by any acute and widespread injurious impingement on the body, including, but not limited to, physical trauma, burn injury, infection (hereinafter sepsis, severe sepsis, blood loss), systemic inflammatory response syndrome (SIRS), acute myocardial infarction, diabetic ketoacidosis, or other thromboembolic events.

[0016] The term "chronic illness" is intended to include any condition that does not require immediate treatment and that is persistent or persistent in its effects or comes with time. The condition may be caused by any persistent disease, including, but not limited to, arthritis, chronic renal failure, liver failure, cancer metastasis, dementia, Parkinson's disease, or schizophrenia.

[0017] As used herein, the term "intensive care" and "organ supportive care" may include, but are not limited to, ventilation therapy (e.g., mechanical ventilation), hemodialysis, vasoconstrictor therapy, fluid therapy, blood exchange therapy with administration of red blood cell concentrates, fresh frozen plasma, platelet concentrates, whole blood, or clotting factor concentrates, systemic antibiotic and / or antiviral and / or antifungal and / or antiprotozoal therapy, parenteral nutrition, granulocyte infusions, T cell infusions, stem cell infusions, anticoagulant and / or antithrombotic therapy including low molecular weight heparins, administration of corticosteroids, strict glycemic control, and treatment with ventricular assist devices, intra-aortic balloon pumps, plasmapheresis, extracorporeal membrane oxygenation, and rotary mechanical circulatory support systems.

[0018] The term "trauma" as used herein means any shock or injury to the body resulting from physical injury such as accident, injury or impact to living tissue caused by an exogenous agent such as blast trauma, crush trauma, blunt trauma, penetrating trauma, trauma caused by chemical injury (overflow, combat or poisoning), radiation or burns.

[0019] As used herein, the term "hyperprocalcitonemia" refers to a condition in which a person has higher than normal levels of the hormone prolactin in their blood. In some embodiments, hyperprocalcitonemia refers to a condition in which a person has blood procalcitonin levels of 0.05 ng / ml or greater.

[0020] As used herein, the terms "treatment" and "treating" refer to the management and care of a patient suffering from or at risk of developing hyperprocalcitonemia. This term is intended to encompass the full range of treatments for this condition, including administration of the phospholipid nanoparticle compositions of the present application for the purposes of ameliorating, alleviating, or reducing symptoms or complications; slowing the progression of the condition, disease, or disorder; curing or eliminating the condition, disease, or disorder; and / or reducing the risk of or preventing the condition, disease, or disorder (including preventing disease recurrence), where "preventing" or "prevention" refers to the management and care of a patient for the purpose of preventing the onset of the condition, disease, or disorder, and should be understood to include administration of the nanoparticle composition to prevent the onset of symptoms or complications. The individual to be treated can be a human or a non-human animal. The individual to be treated according to the present application can be of various ages and / or genders.

[0021] The term "organ failure" refers to altered organ function in an acutely ill patient requiring medical intervention to achieve homeostasis in the body and / or to compensate for loss of function from the failing organ, including but not limited to the heart and blood vessels (heart failure, vasoplegia), lungs (respiratory failure), liver (hepatic failure), kidneys (renal failure), brain (encephalopathy), bones (arthritis), or brain (dementia, encephalitis, or meningitis).

[0022] The term "sepsis" is used in its traditional clinical sense to refer to a systemic inflammatory state (called systemic inflammatory response syndrome (SIRS)) and the presence of a known or suspected infection. "Severe sepsis" is defined as sepsis-induced organ dysfunction or tissue hypoperfusion (e.g., manifested as elevated procalcitonin, tumor necrosis factor, or interleukin-1, vasoplegia, increased lactate, decreased urine output, or altered mental status). Sepsis can lead to severe sepsis, multiple organ dysfunction syndrome / multiple organ failure (MODS), and death.

[0023] The term "systemic inflammatory response syndrome" or "SIRS" is used in its traditional clinical sense to refer to systemic inflammation in response to injury without evidence of an infectious process. SIRS can be diagnosed when two or more of the following criteria are present: 1) body temperature less than 36°C (96.8°F) or more than 38°C (100.4°F); 2) heart rate greater than 90 beats / minute; 3) tachypnea (high respiratory rate) with a respiratory rate greater than 20 breaths / minute or an arterial carbon dioxide partial pressure less than 4.3 kPa (32 mmHg); and 4) a white blood cell count of 4000 cells / mm 3 (4x10 9 pcs / L) or less than 12,000 pcs / mm 3 (12x10 9Presence of more than 10% immature neutrophils (band-shaped nuclei) or more than 10% of neutrophils (cells / L). If infection is suspected or proven (by culture, staining, or polymerase chain reaction (PCR)) along with SIRS, this is, by definition, sepsis. Hyperprocalcitonemia is seen with sepsis (Schuetz et al. Serial Procalcitonin Predicts Mortality in Severe Sepsis Patients: Results From the Multicenter Procalcitonin MOnitoring SEpsis (MOSES) Study. Crit. Care Med. 2017 20(30):Open Access), severe blood loss (Procalcitonin release patterns in a baboon model of trauma and sepsis: relationship to cytokines and neopterin. Crit. Care Med. 2000 28(11):3659-3663), and severe heart failure (Picariello et al. Procalcitonin in patients with acute coronary syndromes and cardiogenic shock submitted to percutaneous coronary intervention. Intern Emerg Med. 2009 4(5):403-408). Interleukin-6 and procalcitonin have been shown to be elevated after injury to the brain and spinal cord and during status epilepticus (Abdulla et al. Neurogenic Originated Inflammatory Response Syndrome: Role in the Neurocritical Patient. J. Neurointensive Care 2022 5(2):39-43). Thus, physiological disruptions induced by infection, blood loss, heart failure, or neuronal injury differ in their initiation. However, once initiation occurs, they all share a common inflammatory component that leads to the production of procalcitonin.

[0024] The term "systemic inflammation" refers to altered organ function in acutely or chronically ill patients due to a non-specific, preserved response of the body (vasculature, immune system, tissues) to infection, non-infectious antigens, trauma, burns, organ / tissue destruction / degeneration / injury, ischemia, hemorrhage, poisoning, and / or malignancy.

[0025] The terms "micelle" and "lipid-loaded micelle (LM)" are used interchangeably herein to refer to aggregates of molecules dispersed in a liquid, including aggregates in which the hydrophilic "head" regions are in contact with the surrounding solvent and the hydrophobic single tail region is sequestered in the center of the micelle, forming a hydrophobic core suitable for containing and delivering hydrophobic substances.

[0026] The term "liposome," as used herein, refers to a vesicular structure composed of lipids with a hydrophilic head group and a tail group containing a long hydrophobic hydrocarbon chain, organized to form a lipid bilayer with an inner aqueous core environment suitable for containing and delivering aqueous substances, and a lipid wall suitable for containing hydrophobic substances, particularly gases such as oxygen.

[0027] The term hydrophobic particle includes micelles and liposomes, but also any particle containing polycyclic compounds with cavities, i.e., molecular cages, that create a hydrophobic space or encapsulate hydrophobic substances or species, such as hydrogels.

[0028] II. Treatment Methods One aspect of the present application relates to a method for treating or preventing hyperprocalcitonemia in a patient, the method comprising administering to the subject an effective amount of a nanoparticle composition of the present application. The inventors of the present application have unexpectedly discovered that administration of a nanoparticle composition of the present application can prevent or reduce hyperprocalcitonemia.

[0029] Based on the vast majority of knowledge in the field, injection of a hydrophobic nanoparticle composition should elevate procalcitonin. Instead, the inventors have found significant and consistent relief. Procalcitonin is a 116-amino acid peptide with an approximate molecular weight of 13.0 kDa. Procalcitonin is expressed in parafollicular cells of the thyroid gland, where it is enzymatically cleaved to produce the calcium-regulating hormone calcitonin. Normally, procalcitonin production is limited, with bloodstream concentrations of <0.05 ng / ml being very low. The enzyme converting procalcitonin to calcitonin is absent in tissues other than the thyroid gland. However, under conditions of severe physiological stress, monocytes and parenchymal cells in many organs can synthesize procalcitonin, resulting in a 100,000-fold increase in blood levels. Elevated procalcitonin levels have been observed in a wide variety of conditions, including sepsis, acute renal failure, chronic renal failure, Alzheimer's disease, vascular dementia, Lewy body dementia, frontotemporal dementia, encephalitis, meningitis, acute respiratory distress syndrome, COVID-19 infection, preeclampsia, lung cancer, colon cancer, ovarian cancer, heart failure, severe blood loss, and trauma. Procalcitonin is considered a marker of disease severity. However, procalcitonin itself has also been shown to have adverse effects. Elevated procalcitonin occurs as a result of increased levels of proinflammatory proteins such as tumor necrosis factor and interleukin-6 (Whang et al. Procalcitonin and proinflammatory cytokine Interactions in Sepsis. Shock 2000. 14(1):73-78 and Nijsten et al. Procalcitonin behaves as a fast-responding acute phase protein in vivo and in vitro. Crit. Care Med. 2000 28(2):458-461). Cai et al. (Mediators of Inflammation 2010 Volume 2010 Article ID 642462 (open access)) showed that both sepsis and severe blood loss induce tumor necrosis factor and high mobility group box 1 protein.Furthermore, Reidl et al. (Crit. Care Med. 2000. 28(11):3659-3663) showed that procalcitonin is increased in both sepsis and severe blood loss.

[0030] Hierholzer et al. (Am. J. Physiol. 1998 275(3):L611-621) also demonstrated that severe blood loss leads to an increase in interleukin-6. Injection of hydrophobic nanoparticles composed of liposomes and micelles, such as Intralipid, has been shown to increase blood levels of pro-inflammatory mediators. Krough-Madesen et al. (Am. J. Physiol Endocrinol Metab 2008,294(2)E371-379) demonstrated that after endotoxin infusion, Intralipid increased the production of pro-inflammatory mediators, such as tumor necrosis factor and interleukin-6. Lou et al. (Mol. Nutr. Food Res. 2021 65(5)) found that Intralipid infusion increased many pro-inflammatory mediators, including interleukin-6. As shown by Duncan et al. (FASEB Journal 2019 33(51)), injection of Intralipid into pregnant rats increased pro-inflammatory mediators. Because of the increase in pro-inflammatory mediators by Intralipid, one skilled in the art would expect that injection of the nanoparticle composition of the present application would lead to an increase in procalcitonin. Furthermore, because the nanoparticle composition increases pro-inflammatory mediators, one skilled in the art would not administer the nanoparticle composition of the present application to patients, expecting a decrease in procalcitonin with its harmful effects. Contrary to expectations raised by the literature, the inventors have found a consistent decrease in procalcitonin after injection of the nanoparticle composition of the present application. It is also noteworthy that no significant adverse effects attributable to the nanoparticle composition of the present application were observed. Therefore, the unexpected decrease in procalcitonin, which itself promotes organ damage, by the nanoparticle composition of the present application has significant therapeutic applications.

[0031] The nanoparticle compositions of the present application can be used to treat or prevent hyperprocalcitonemia caused by several different disease states affected by tissue injury, including, but not limited to, sepsis, major trauma, burns, pancreatitis, aspiration syndrome, extracorporeal circulation (e.g., cardiac bypass), multiple blood transfusions, ischemia-reperfusion injury, autoimmune disease, severe blood loss, heat-induced disease, eclampsia, and intoxication / toxicity. In some embodiments, the nanoparticle compositions of the present application are used to treat or prevent hyperprocalcitonemia caused by sepsis caused by influenza virus or coronavirus (such as SARS, MERS, and COVID-19 viruses) infection.

[0032] A chronic pro-inflammatory state is a widespread characteristic of aging. This chronic low-grade inflammation, occurring in the absence of overt infection, has been defined as "inflammaging" and represents a significant risk factor for morbidity and mortality in older adults. The nanoparticle compositions of the present application can be used to treat aging. In some embodiments, the method comprises administering to a subject in need of treatment an effective amount of a nanoparticle composition comprising: an amphiphilic emulsifier in an amount of 0.1% to 100% (w / v); a lipid-soluble or hydrophobic component in an amount of 0 to 35% (w / v); a polar liquid carrier; and one or more electrolytes, wherein the nanoparticle composition comprises liposomes and / or micelles having a diameter in the range of 1 to 800 nm.

[0033] The nanoparticle compositions of the present application may be administered intravenously, intraarterially, intraosseously, or intracardially to a subject in need of such treatment. In certain embodiments, the nanoparticle compositions may be administered in volumes of 50-5000 ml, 50-4000 ml, 50-3000 ml, 50-2000 ml, 50-1000 ml, 50-500 ml, 100-5000 ml, 100-4000 ml, 100-3000 ml, 100-2000 ml, 100-1000 ml, 100-500 ml, 200-5000 ml, 200-4 In some embodiments, the nanoparticle composition is administered in an amount equivalent to about 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, or 90% of the subject's normal blood volume for 30 seconds to 24 hours. In some embodiments, the nanoparticle compositions of the invention are administered in multiple doses spaced 2, 4, 8, 12, 24, or 48 hours apart.

[0034] In some embodiments, the nanoparticle composition is delivered at a rate of 0.1-5000 ml / min, 0.1-2000 ml / min, 0.1-1000 ml / min, 0.1-500 ml / min, 0.1-200 ml / min, 0.1-100 ml / min, 0.1-50 ml / min, 0.1-20 ml / min, 0.1-10 ml / min, 0.1-5 ml / min, 0.1-2 ml / min, 0.1-1 ml / min, 1-5000 ml / min, 1-2000 ml / min, 1-1000 ml / min, 1-500 ml / min, 1-200 ml / min, 1-100 ml / min, 1-100 ml / min, 1-200 ml / min, 1-100 ml / min, 1-200 ml / min, 1-100 ml / min, 1-500 ml / min, 1-200 ml / min, 1-1 ... ml / min.1~50ml / min, 1~20ml / min, 1~10ml / min, 1~5ml / min, 1~2ml / min, 2~5000ml / min, 2~2000ml / min, 2~1000ml / min, 2~500ml / min, 2~200ml / min, 2~1 00ml / min.2~50ml / min, 2~20ml / min, 2~10ml / min, 2~5ml / min, 5~5000ml / min, 5~2000ml / min, 5~1000ml / min, 5~500ml / min, 5~200ml / min, 5~100ml / min.It is administered at a rate of 5 to 50 ml / min, 5 to 20 ml / min, 5 to 10 ml / min, 10 to 5000 ml / min, 10 to 4000 ml / min, 10 to 3000 ml / min, 10 to 2000 ml / min, 10 to 1000 ml / min, 10 to 500 ml / min, 10 to 200 ml / min, 10 to 100 ml / min, 10 to 50 ml / min, 20 to 5000 ml / min, 20 to 4000 ml / min, 20 to 3000 ml / min, 20 to 2000 ml / min, 20 to 1000 ml / min, 20 to 500 ml / min, 20 to 200 ml / min, 20 to 100 ml / min, 20 to 50 ml / min, 50 to 5000 ml / min, 50 to 4000 ml / min, 50 to 3000 ml / min, 50 to 2000 ml / min, 50 to 1000 ml / min, 50 to 500 ml / min, 50 to 200 ml / min, 50 to 100 ml / min, 100 to 5000 ml / min, 100 to 4000 ml / min, 100 to 3000 ml / min, 100 to 2000 ml / min, 100 to 1000 ml / min, 100 to 500 ml / min, 100 to 200 ml / min, 200 to 5000 ml / min, 200 to 4000 ml / min, 200 to 3000 ml / min, 200 to 2000 ml / min, 200 to 1000 ml / min, 200 to 500 ml / min, 500 to 5000 ml / min, 500 to 4000 ml / min, 500 to 3000 ml / min, 500 to 2000 ml / min, 500 to 1000 ml / min, 1000 to 5000 ml / min, 1000 to 4000 ml / min, 1000 to 3000 ml / min, 1000 to 2000 ml / min, 2000 to 5000 ml / min, 2000 to 4000 ml / min, 2000 to 3000 ml / min, 3000 to 5000 ml / min, 3000 to 4000 ml / min or 4000 to 5000 ml / min.

[0035] In some embodiments, the nanoparticle composition is provided without oxygen. In other embodiments, the nanoparticle composition is an oxygenated nanoparticle composition. In some embodiments, the nanoparticle composition is an oxygenated nanoparticle composition having an oxygen content of 2-50, 2-40, 2-30, 2-20, 2-10, 2-5, 5-50, 5-40, 5-30, 5-20, 5-10, 10-50, 10-40, 10-30, 10-20, 15-50, 15-40, 15-30, 15-20, 20-50, 20-40, 20-30, 25-50, 25-40, 25-30, 30-50, 30-40, or 40-50 ml O2 / 100 ml nanoparticle composition.

[0036] Other hemodynamic parameters, such as brain, kidney, heart, muscle, spleen or other tissue perfusion, cardiac output, systolic blood pressure, diastolic blood pressure, mean pulse pressure, cardiac output index, mitochondrial oxidative phosphorylation followed by near-infrared spectroscopy or other means, blood lactate or membrane polarization, can also be used to determine the "effective amount" of the nanoparticle composition required to treat hyperprocalcitonemia in a subject.

[0037] In some embodiments, the method further comprises administering to the subject an additional agent. The additional agent may be administered prior to, concurrently with, or after administration of the nanoparticles of the present application. Examples of the additional agent include, but are not limited to, cardioplegic and inotropic agents, procalcitonin antibodies, the calcitonin gene-related peptide antagonist olcegepant, and sitagliptin, a dipeptidyl-peptidase 4 inhibitor for blocking procalcitonin signaling or activation.

[0038] III. Nanoparticle Compositions In one embodiment, a nanoparticle composition for treating or preventing hyperprocalcitonemia comprises one or more amphiphilic emulsifiers, a lipophilic or hydrophobic component, a polar liquid carrier, and one or more electrolytes. The amphiphilic emulsifiers form lipophilic or hydrophobic-loaded micelles (LMs) having a lipophilic core surrounded by a polar liquid carrier, and / or liposomes containing a lipid bilayer and a hydrophilic interior (or core).

[0039] In some embodiments, the nanoparticle compositions of the present application comprise LMs and liposomes having diameters in the range of 1-1000 nm, 1-800 nm, 1-500 nm, 1-400 nm, 1-300 nm, or 1-200 nm, as determined by electron microscopy.

[0040] In some embodiments, the nanoparticle compositions of the present application have a particle size of (1) 30-800 nm, 30-500 nm, 30-400 nm, 30-300 nm, 30-200 nm, 30-150 nm, 30-120 nm, 30-100 nm, 30-80 nm, 40-500 nm, 40-400 nm, 40-300 nm, 40-200 nm, 40-150 nm, 40-120 nm, 40-100 nm, 40-80 nm, 50-500 nm, 50-400 nm, 50-300 nm, 50-200 nm, 50-150 nm, 50-120 nm, 50-100 nm, 50-80 nm, 100-50 nm, or less, as determined by electron microscopy. and (2) LMs having a diameter of 1-30 nm, 1-25 nm, 1-20 nm, 1-15 nm, 1-10 nm, 3-30 nm, 3-25 nm, 3-20 nm, 3-15 nm, 3-10 nm, 5-30 nm, 5-25 nm, 5-20 nm, 5-15 nm, 5-10 nm, 1-30 nm, 7-25 nm, 7-20 nm, 7-15 nm, 7-10 nm, 10-30 nm, 10-25 nm, 10-20 nm, or 10-15 nm, as determined by electron microscopy.

[0041] In some embodiments, the nanoparticle compositions herein have a particle size of 1-800 nm, 1-500 nm, 1-300 nm, 1-100 nm, 1-80 nm, 1-50 nm, 1-40 nm, 1-30 nm, 1-25 nm, 1-20 nm, 1-15 nm, 1-10 nm, 1-5 nm, 5-800 nm, 5-500 nm, 5-300 nm, 5-100 nm, 5-80 nm, 5-50 nm, 5-40 nm, 5-30 nm, 5-30 nm, 5-40 nm, 5-50 nm, 5-60 nm, 5-60 nm, 5-70 nm, 5-80 nm, 5-90 nm, 5-90 nm, 5-100 nm, 5-120 nm, 5-140 nm, 5-160 nm, 5-180 nm, 5-20 nm, 5-25 nm, 5-30 nm, 5-30 nm, 5-40 nm, 5-50 nm, 5-60 nm, 5-100 nm, 5-160 nm, 5-20 nm, 5-30 nm, 5-40 nm, 5-50 nm, 5-60 nm, 5-100 nm, 5-120 nm, 5-20 nm, 5-25 nm, 5-30 nm, 5-30 nm, 5-40 nm, 5-5 ... nm, 5~25nm, 5~20nm, 5~15nm, 5~10nm, 10~800nm, 10~500nm, 10~300nm, 10~100nm, 10~80nm, 10~50nm, 10~40nm, 10~3 0nm, 10~25nm, 10~20nm, 15~800nm, 15~500nm, 15~300nm, 15~100nm, 15~80nm, 15~50nm, 15~40nm, 15~30nm, 15~25nm , 15~20nm, 20~800nm, 20~500nm, 20~300nm, 20~100nm, 20~80nm, 20~50nm, 20~40nm, 20~30nm, 20~25nm, 25~800nm, 2 5~500nm, 25~300nm, 25~100nm, 25~80nm, 25~50nm, 25~40nm, 25~30nm, 30~800nm, 30~500nm, 30~300nm, 30~100nm, 3 The nanoparticle compositions of the present application comprise nanoparticles (including both micelles and liposomes) having an average particle size of 0-80 nm, 30-50 nm, 30-40 nm, 40-800 nm, 40-500 nm, 40-300 nm, 40-100 nm, 40-80 nm, 40-50 nm, 50-800 nm, 50-500 nm, 50-300 nm, 50-100 nm, 50-80 nm, 80-800 nm, 80-500 nm, 80-300 nm, or 80-100 nm. In some embodiments, the nanoparticle compositions of the present application comprise nanoparticles having an average particle size of 16-18 nm, 15-19 nm, or 14-20 nm, as determined by electron microscopy.

[0042] In some embodiments, the nanoparticle compositions herein have a particle size of 10-1000 nm, 10-800 nm, 10-500 nm, 10-300 nm, 10-200 nm, 10-150 nm, 10-120 nm, 10-100 nm, 10-90 nm, 10-70 nm, 10-50 nm, 10-30 nm, 30-1000 nm, 30-800 nm, 30-500 nm, 30-300 nm, 30-200 nm, 30-150 nm, 30-120 nm, 30-100 nm, 30-300 nm, 30-200 nm, 30-150 nm, 30-120 nm, 30-100 nm, 30-300 nm, 30-400 nm, 30-500 nm, 30-300 nm, 30-200 nm, 30-150 nm, 30-120 nm, 30-100 nm, 30-400 nm, 30-500 nm, 30-300 nm, 30-200 nm, 30-150 nm, 30-120 nm, 30-100 nm, 30-3 ...500 nm, 30-600 nm, 30-600 nm, 30-700 nm, 30 ~90nm, 30~70nm, 30~50nm, 50~1000nm, 50~800nm, 50~500nm, 50~300nm, 50~200nm, 50~150nm, 50~120nm, 50~100nm, 50~90n m, 50~70nm, 70~1000nm, 70~800nm, 70~500nm, 70~300nm, 70~200nm, 70~150nm, 70~120nm, 70~100nm, 70~90nm, 80~1000nm, 80~800nm, 80~500nm, 80~300nm, 80~200nm, 80~150nm, 80~120nm, 80~100nm, 80~90nm, 90~1000nm, 90~800nm, 90~500nm, 9 0~300nm, 90~200nm, 90~150nm, 90~120nm, 90~100nm, 100~1000nm, 100~800nm, 100~500nm, 100~300nm, 100~200nm, 100~15 In some embodiments, the nanoparticle compositions of the present application comprise nanoparticles (including both micelles and liposomes) having an average diameter of 92-96 nm, 90-98 nm, or 85-105 nm.

[0043] Lipid-soluble or hydrophobic components are dispersed in a polar liquid carrier to form nanoemulsions containing unilamellar micelles with polar exteriors and hydrophobic interior spaces filled with the lipophilic or hydrophobic components and / or other hydrophobic molecules, and bilayer liposomes with polar exteriors and hydrophilic interior spaces. Because hydrophobic gases, such as oxygen and nitric oxide (NO), preferentially dissolve in the lipid core of the micelles compared to water or other aqueous environments, the nanoparticle compositions of the present application provide the ability to retain oxygen and other hydrophobic gases in body tissues.

[0044] The solubility of hydrophobic gases in the lipid-soluble or hydrophobic core facilitates the uptake and transport of these gases into tissues. Endogenously produced gases, carbon monoxide, nitric oxide, and hydrogen sulfide, can also be retained in emulsions for the modulation of vascular tone and apoptotic processes.

[0045] In some embodiments, the nanoparticle composition is an oxygenated nanoparticle composition that enhances aerobic metabolism, ie, an oxygen content of 1-50, 1-40, 1-30, 1-20, 1-10, 1-5, 1-2, 2-50, 2-40, 2-30, 2-20, 2-10, 2-5, 5-50, 5-40, 5-30, 5-20, 5-10, 10-50, 10-40, 10-30, 10-20, 15-50, 15-40, 15-30, 15-20, 20-50, 20-40, 20-30, 25-50, 25-40, 25-30, 30-50, 30-40, or 40-50 ml O2 / 100 ml nanoparticle composition.

[0046] In some embodiments, the nanoparticle composition comprises NO in an amount of 1-50, 1-40, 1-30, 1-20, 1-10, 1-5, 1-2, 2-50, 2-40, 2-30, 2-20, 2-10, 2-5, 5-50, 5-40, 5-30, 5-20, 5-10, 10-50, 10-40, 10-30, 10-20, 15-50, 15-40, 15-30, 15-20, 20-50, 20-40, 20-30, 25-50, 25-40, 25-30, 30-50, 30-40, or 40-50 ml NO / 100 ml nanoparticle composition.

[0047] Xenon and argon are hydrophobic gases that may provide brain protection in conditions such as epileptic seizures. In some embodiments, the nanoparticle compositions include Xe or Ar, or both, in an amount of 1-50, 1-40, 1-30, 1-20, 1-10, 1-5, 1-2, 2-50, 2-40, 2-30, 2-20, 2-10, 2-5, 5-50, 5-40, 5-30, 5-20, 5-10, 10-50, 10-40, 10-30, 10-20, 15-50, 15-40, 15-30, 15-20, 20-50, 20-40, 20-30, 25-50, 25-40, 25-30, 30-50, 30-40, or 40-50 ml O2 / 100 ml nanoparticle composition.

[0048] In some embodiments, the nanoparticle compositions of the present application further comprise an inhibitor of apoptosis (e.g., Z-VAD-FMY, an apoptosis inhibitor peptide), a protector of mitochondrial integrity (e.g., cyclosporin A, an inhibitor of mitochondrial inner pore opening), a modulator of signal transduction, such as diacylglycerol or cyclic GMP, or an antioxidant, such as coenzyme Q10.

[0049] When nanoparticles having liposomes with an average diameter of less than 30 nm are used, the liposomes can cross the endothelial cell layer and enter the interstitial space. Such liposomes can be used in situations where the permeability of the vascular space is not or is increased, or to promote cellular absorption of lipid-soluble or hydrophobic mediators, or to promote the entry of molecules or cellular components that can selectively modulate intracellular mechanisms.

[0050] In certain cases, the nanoparticle compositions of the present application can exert penetration and / or absorb mediators of tissue injury, such as prostaglandins, nitric oxide, leukotrienes, and thromboxanes, as well as other lipid-soluble or hydrophobic mediators, such as platelet-activating factor. Thus, in some cases, the nanoparticles of the present application can absorb toxic molecules produced by patients with hyperprocalcitonemia. For example, acute lung injury and red blood cell deformability can result from lymphatic factors produced in the intestinal and thoracic duct lymph nodes. Other toxic molecules include, but are not limited to, leukotrienes, prostaglandins, nitric oxide, endotoxin, and tumor necrosis factor (TNF). The nanoparticles in the nanoparticle compositions enable the effective absorption of lipid-soluble or hydrophobic chemical mediators. In some cases, absorption can be the result of electrostatic interactions. In other cases, the nanoparticles can be loaded with antagonists to toxic chemical mediators, such as antibodies against endotoxin.

[0051] For example, in patients with hyperprocalcitonemia, where capillary leakage causes increased vascular wall permeability, the small size of these phospholipid nanoparticles (PN) facilitates their penetration into the interstitial space, which would otherwise be restricted by larger structures. Capillary leakage is caused by endothelial cell death and the action of neutrophils, which are mediated by cytokines such as IL-1 and TNF, as well as nitric oxide. Neutrophils adhere to damaged endothelial cells and release reactive oxygen species and cell wall-damaging enzymes such as myeloperoxidase. Nanoparticles can reach the interstitium via capillary leakage and, for example, exert anti-inflammatory effects within the interstitial space.

[0052] Preferably, the nanoparticle compositions are formulated to contain LMs and / or liposomes that are stable at room temperature (e.g., 25°C) or 5°C for at least 3 days, 7 days, 2 weeks, 4 weeks, 12 weeks, 20 weeks, 180 days, 30 weeks, 40 weeks, 1 year, or more than 1 year. Stability can be determined by measuring changes in particle size. Unstable emulsions have micelles that coalesce to form larger diameter micelles. In certain preferred embodiments, the nanoparticle compositions are stable at room temperature for at least 4 weeks.

[0053] In some embodiments, the nanoparticle composition is formed from soybean oil in an amount of 5% to 40% (w / v) and lecithin in an amount of 0.1% to 18% (w / v). In some embodiments, the nanoparticle composition further comprises NaCl at a final concentration of 50 to 200 mM. In some embodiments, the nanoparticle composition further comprises glycerin in an amount of 1 to 5%. In one embodiment, the nanoparticle composition comprises 10% (w / v) soybean oil, 0.6% (w / v) egg lecithin, 1.13% (w / v) glycerin, and 77 mM NaCl. In another embodiment, the nanoparticle composition comprises 20% (w / v) soybean oil, 1.2% (w / v) egg lecithin, and 2.25% (w / v) egg lecithin. In another embodiment, the nanoparticle composition comprises 20% (w / v) soybean oil, 1.2% (w / v) egg lecithin, and 2.25% (w / v) egg lecithin and 77 mM NaCl.

[0054] In some embodiments, the composition is formed from soybean oil in an amount of 10% to 40% (w / v), preferably 15% to 35%, lecithin in an amount of 1% to 18% (w / v), preferably 10% to 15%, sodium chloride and sodium lactate as electrolytes (total electrolyte composition is 50 mM to 200 mM), histidine in an amount of 0.1 mM to 10 mM, and water, wherein the lecithin forms (1) lipid-loaded micelles in aqueous solution that have a lipophilic or hydrophobic core, and the resulting micelles have an average diameter of 1 to 150 nm, preferably 40 nm to 120 nm, as determined by dynamic light scattering, and are stable at room temperature for at least 4 weeks; and (2) liposomes with a diameter in the range of 1 to 25 nm, as determined by electron microscopy.

[0055] In another embodiment, the nanoparticle composition comprises 10-40% (w / v) soybean oil and 6-18% (w / v) egg lecithin or soybean lecithin. In some embodiments, the nanoparticle composition further comprises 0.6% (w / v) NaCl, 0.385% (w / v) sodium lactate (L), and 0.155% (w / v) histidine. In some embodiments, the nanoparticle composition comprises 20-30% (w / v) soybean oil, 12% (w / v) egg lecithin or soybean lecithin, 0.6% (w / v) NaCl, 0.385% (w / v) sodium lactate (L), and 0.155% (w / v) histidine.

[0056] In another embodiment, the nanoparticle composition comprises 20% (w / v) soybean oil, 12% (w / v) egg lecithin or soybean lecithin, 0.6% (w / v) NaCl, 0.385% (w / v) sodium lactate (L), and 0.155% (w / v) histidine, prepared under conditions to form nanoparticles (including liposomes and micelles) having an average diameter of 250-300 nm as determined by dynamic light scattering. In some embodiments, the nanoparticles comprise liposomes having a diameter in the range of 1-25 nm or 7-20 nm as measured by electron microscopy, and micelles having a diameter in the range of 30-130 nm or 40-100 nm as measured by electron microscopy.

[0057] In another embodiment, the nanoparticle composition comprises 30% (w / v) soybean oil, 12% (w / v) egg lecithin or soybean lecithin, 0.6% (w / v) NaCl, 0.385% (w / v) sodium lactate (L), and 0.155% (w / v) histidine, prepared under conditions to form nanoparticles (including liposomes and micelles) having an average diameter of 80-120 nm as measured by dynamic light scattering. In some embodiments, the nanoparticles comprise liposomes having a diameter in the range of 1-25 nm or 7-20 nm as measured by electron microscopy, and micelles having a diameter in the range of 30-130 nm or 40-100 nm as measured by electron microscopy.

[0058] Other oils, such as chia bean, pumpkin seed, or oils from other sources, may be used. In certain embodiments, the nanoparticle composition may further comprise about 2-40% (w / v), about 2-20% (w / v), about 4-10% (w / v), or about 5% (w / v) of albumin or albumin polymer, or albumin polymer complexed with an amino acid or peptide, which is added to the nanoparticle composition after micelle formation. In other embodiments, the hydrophobic or hydrophilic component is retained within the red blood cell ghosts.

[0059] In certain embodiments, the LM comprises 10-40% (w / w) of the nanoparticle composition, while the liposomes comprise 5-30% (w / w) of the nanoparticle composition. In some embodiments, the LM is made using soybean oil and the liposomes are made using chia bean oil, which has stronger anti-inflammatory effects than soybean oil.

[0060] In certain embodiments, the nanoparticle compositions of the present application comprise a fat-soluble or hydrophobic component selected from the group consisting of soybean oil, chia bean oil, and algae oil, an emulsifier selected from the group consisting of phospholipids and α-phosphatidylcholines, and an amino acid or n-acetylamino acid at a final concentration of 0.2-20 mM, 0.5-10 mM, 0.5-5 mM, or 0.5-2 mM.

[0061] In certain embodiments, the final amino acid concentration of the nanoparticle composition is 0.000001-10 mM, 0.01-10 mM, 0.1-10 mM, 0.2-10 mM, 0.5-10 mM, 1-10 mM, 2.5-10 mM, 5-10 mM, or 7.5-10 mM. In certain embodiments, the final amino acid concentration of the nanoparticle composition is 0.001, 0.01, 0.1, 0.2, 0.5, 1, 2.5, 5, 7.5, or 10 mM. The emulsifier:lipid-soluble or hydrophobic component ratio (w / w) can range from about 1:400 to about 1:1, preferably from about 1:200 to about 1:50. In one embodiment, the emulsifier:lipid-soluble or hydrophobic component ratio (w / w) is about 1:100. In another embodiment, the emulsifier:lipophilic or hydrophobic component ratio (w / w) is about 1.2:100.

[0062] In some embodiments, the nanoparticle composition consists essentially of liposomes and does not include fat-soluble or hydrophobic components, such as soybean oil.

[0063] In some embodiments, the nanoparticle compositions comprise one or more active pharmaceutical ingredients or drugs (e.g., nucleic acids, proteins, low molecular weight drugs, etc.) in the LMs and / or liposomes. The active pharmaceutical ingredients or drugs can be incorporated into the lipid-soluble or hydrophobic core of the LMs or liposomes or into the hydrophilic core of the liposomes.

[0064] In one embodiment, the nanoparticle composition comprises soybean oil, egg phospholipids and amino acids, beta-endorphin or other modulators acting at suprafetomolar concentrations at a final concentration of 0.1 fetomolar (fM) to 10 mM.

[0065] The nanoparticle compositions of the present application are free of hemoglobin, hemoglobin derivatives, perfluorocarbons, and perfluorocarbon derivatives. As used herein, a composition is "free of hemoglobin, hemoglobin derivatives, perfluorocarbons, and perfluorocarbon derivatives" if the composition does not contain hemoglobin, hemoglobin derivatives, perfluorocarbons, and perfluorocarbon derivatives, or if the composition contains hemoglobin, hemoglobin derivatives, perfluorocarbons, and perfluorocarbon derivatives at a level of less than 0.1% w / v.

[0066] The nanoparticle compositions of the present application typically contain Ca ++ , K. + and Mg ++ Al is not added. +++ In certain embodiments, Ca ++ and K. + is added to the nanoparticle composition immediately prior to use (e.g., within 24 hours prior to use). ++ is premixed with the nanoparticle composition. +++ is toxic to bone, brain, hematopoiesis, heme synthesis, globulin synthesis, iron absorption and metabolism, and fetal growth, so the Al content of all oils and other components +++ In certain embodiments, the nanoparticle composition contains Al at a concentration of less than 25 mg / L, 20 mg / L, 10 mg / L, or 5 mg / L. +++ In other embodiments, the nanoparticle composition contains Al +++ Free, i.e., undetectable by conventional methods.

[0067] In certain embodiments, the micelles in the nanoparticle compositions of the present application are free-floating micelles that are not encapsulated in any type of particle. Furthermore, the walls of the micelles are composed of either a monolayer or bilayer of amphiphilic emulsifier molecules, allowing the micelles to easily fuse with cell membranes of tissues that come into contact with the nanoparticle compositions. Furthermore, the micelles in the nanoparticle compositions of the present application are free of hemoglobin, hemoglobin derivatives, perfluorocarbons, and perfluorocarbon derivatives.

[0068] Amphiphilic emulsifiers An amphiphilic emulsifier can be any amphiphile or molecule that has its hydrophobic tail in the lipophilic or hydrophobic core of the micelle and its hydrophilic end in contact with the polar carrier.

[0069] As used herein, the term "amphiphile" refers to a chemical compound that possesses both hydrophilic and lipophilic or hydrophobic properties. Examples of amphiphiles include, but are not limited to, natural amphiphiles, such as phospholipids, cholesterol, glycolipids, fatty acids, bile acids, and saponins; and synthetic amphiphiles, such as amphipathic peptides.

[0070] Examples of phospholipids include natural or synthetic phospholipids, such as phosphatidylcholine, phosphatidylethanolamine, phosphatidylserine, phosphatidic acid, phosphatidylglycerol, phosphatidylinositol, lysophosphatidylcholine, sphingomyelin, egg yolk lecithin, soybean lecithin, and hydrogenated phospholipids.

[0071] Examples of glycolipids include glyceroglycolipids and glycosphingolipids. Examples of glyceroglycolipids include digalactosyl diglycerides (digalactosyl dilauroylglyceride, digalactosyl dimyristoylglyceride, digalactosyl dipalmitoylglyceride, and digalactosyl distearoylglyceride) and galactosyl diglycerides (galactosyl dilauroylglyceride, galactosyl dimyristoylglyceride, galactosyl dipalmitoylglyceride, and galactosyl distearoylglyceride, etc.). Examples of glycosphingolipids include galactosylcerebroside, lactosylcerebroside, and ganglioside.

[0072] Examples of sterols include cholesterol, cholesterol hemisuccinate, 3β-[N--(N',N'-dimethylaminoethane)carbamoyl]cholesterol, ergosterol, and lanosterol.

[0073] In one embodiment, the emulsifier comprises egg phospholipids or egg yolk lecithin, hi another embodiment, the emulsifier is soy lecithin or alpha-phosphatidylcholine.

[0074] In other embodiments, the emulsifier accounts for 0.1-100%, 0.1-90%, 0.1-80%, 0.1-70%, 0.1-60%, 0.1-50%, 0.1-40%, 0.1-30%, 0.1-20%, 0.1-15%, 0.1-10%, 0.1-5%, 0.1-2%, 0.3-100%, 0.3-90%, 0.3-80%, 0.3-70%, 0.3-60%, 0.3-50%, 0.3-40%, 0.3-30%, 0.3-20%, 0.3 ~15%, 0.3~10%, 0.3~5%, 0.3~2%, 0.6~100%, 0.6~90%, 0.6~80%, 0.6~70%, 0.6~60%, 0.6~50%, 0.6~40%, 0.6~30%, 0.6~20%, 0.6~15%, 0.6~10%, 0.6~5%, 0.6~2%, 2~100%, 2~90%, 2~80%, 2~70%, 2~60%, 2~50%, 2~40%, 2~30%, 2~20%, 2~15%, 2~10%, 2~5%, 6~100%, 6~90%, 6~80%, 6~70%, 6~60%, 6~50%, 6~40%, 6~30%, 6~20%, 6~15%, 6~10%, 10~100%, 10~90%, 10~80%, 10~70%, 10~60%, 10~50%, 10~40%, 10~30%, 10~20%, 10~15%, 15~100%, 15~90%, 15~80%, 15~70%, 15~60%, 15~50%, 15~40%, 15~30%, 15~20%, It may comprise 20 to 100%, 20 to 90%, 20 to 80%, 20 to 70%, 20 to 60%, 20 to 50%, 20 to 40%, 20 to 30%, 30 to 100%, 30 to 90%, 30 to 80%, 30 to 70%, 30 to 60%, 30 to 50%, 30 to 40%, 40 to 100%, 40 to 90%, 40 to 80%, 40 to 70%, 40 to 60%, 40 to 50%, 50 to 100%, 50 to 90%, 50 to 80%, 50 to 70%, or 50 to 60% (w / v or v / v). In some embodiments, the emulsifier may comprise more than 1%, 2%, 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, or 95% (w / v or v / v) of the nanoparticle composition.In certain embodiments, the emulsifier is present at a level of about 1%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15%, 16%, 18%, 20% (w / v or v / v) of the nanoparticle composition, or any other range between any two of these recited integers. In other embodiments, the emulsifier is present at a level of about 7-9%, 9-11%, 11-13%, 13-15%, 15-17%, 17-19%, 10-14%, 9-15%, or 8-16% (w / v or v / v) of the nanoparticle composition, or any other range between any two of these recited integers. In still other embodiments, the upper and / or lower limits of the emulsifier are defined by any of the recited concentrations described herein.

[0075] In certain preferred embodiments, the emulsifier is lecithin, such as egg yolk lecithin or soybean lecithin, in one of the amounts or ranges described above.

[0076] Lipid-soluble or hydrophobic ingredients As used herein, the term "lipid-soluble component" refers to a lipid-soluble substance, whether natural or unnatural. Examples of lipid-soluble components include, but are not limited to, fatty acyl, glycerolipids, phospholipids, sphingolipids, sterol lipids, prenol lipids, saccharolipids, polyketides, unnatural lipids, cationic lipids, amphiphilic alkylamino acid derivatives, adialkyldimethylammonium, polyglycerol alkyl ethers, polyoxyethylene alkyl ethers, tri-n-octylamine, boric acid, tris(3,5-dimethyl-4-heptyl) esters, triglycerides, diglycerides, and other acylglycerols, such as tetraglycerol, pentaglycerol, hexaglycerol, heptaglycerol, octoglycerol, nonaglycerol, and decaglycerol, hydrophobic peptides, hydrophobic polysaccharides, silicones, lipopeptides, cyclopeptides, and mixtures thereof. In certain embodiments, the fat-soluble or hydrophobic component comprises soybean oil, chia bean oil, or algae oil.

[0077] In one embodiment, the hydrophobic component is soybean oil.The hydrophobic component can also be derived from chia beans, which have a high concentration of anti-inflammatory omega-3 fatty acids.Soybean oil is thrombogenic and procoagulant, and therefore is preferred when clotting is desired.After bleeding is no longer a problem, oils rich in omega-3 fatty acids are advantageous because they have anticoagulant properties.Oils rich in omega-3 fatty acids include, but are not limited to, chia oil, algae oil, pumpkin oil, flaxseed oil or fish oil.

[0078] In certain embodiments, the fat-soluble or hydrophobic component comprises an unsaturated fatty acid having one or more alkenyl functional groups in a cis or trans configuration. The cis configuration means that adjacent hydrogen atoms or other groups are on the same side of the double bond. In the trans configuration, these moieties are on different sides of the double bond. The rigidity of the double bond restricts its conformation, and in the case of the cis isomer, it bends the chain and limits the conformational freedom of the fatty acid. Generally, the more double bonds there are, the less flexible the chain becomes. If a chain has many cis bonds, it will bend more in its most accessible conformation. For example, oleic acid has one double bond and a "kink" in it, while linoleic acid has two double bonds and a more pronounced bend. Alpha-linolenic acid has three double bonds and favors a hooked shape. This effect is limited in certain circumstances, for example, when the lipid is part of a phospholipid in a lipid bilayer or a triglyceride in a lipid droplet, the cis bond may limit the ability of the fatty acids to pack closely together and thus affect the melting point of the membrane or lipid. In some embodiments, the lipophilic or hydrophobic component comprises up to 1%, 2%, 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 99% (w / v or v / v) of unsaturated fatty acids having one or more alkenyl functional groups in the cis configuration.

[0079] Examples of cis-unsaturated fatty acids include obtusilic acid, linderic acid, tsuzuic acid, palmitoleic acid, oleic acid, elaidic acid, vaccenic acid, petroselinic acid, gadoleic acid, eicosenoic acid, erucic acid, cetoleic acid, nervonic acid, ximenic acid, and lumepueic acid. acid); n-3 unsaturated fatty acids such as α-linolenic acid, stearidonic acid, eicosatetraenoic acid, eicosapentaenoic acid, docosapentaenoic acid, and docosahexaenoic acid; n-6 unsaturated fatty acids such as linoleic acid, linoelaidic acid, γ-linolenic acid, bis-homo-γ-linolenic acid, and arachidonic acid; conjugated fatty acids such as conjugated linoleic acid and α-eleostearic acid; fatty acids having a double bond at the 5-position, such as pinolenic acid, siadonic acid, juniperic acid, and columbic acid; polyunsaturated fatty acids other than those mentioned above, such as heliconic acid, moroctic acid, clupanodonic acid, and nisinic acid; branched fatty acids such as isobutyric acid, isovaleric acid, iso-acids, and anti-iso-acids; hydroxy fatty acids such as α-hydroxy acids, β-hydroxy acids, mycolic acids, and polyhydroxy acids; epoxy fatty acids; keto fatty acids; and cyclic fatty acids. In certain embodiments, the lipophilic or hydrophobic component also includes an amphiphilic molecule.

[0080] The lipophilic or hydrophobic component may comprise approximately 0-80%, 1-80%, 1-70%, 1-60%, 1-50%, 1-40%, 1-30%, 1-20%, 5-80%, 5-70%, 5-60%, 5-50%, 5-40%, 5-30%, 5-20%, 10-80%, 10-70%, 10-60%, 10-50%, 10-40%, 10-30%, 10-20%, 15-80%, 15-70%, 15-60%, 15-50%, 15-40%, 15-30%, 15-40% or 15-50% of the nanoparticle composition. %, 15-20%, 20-80%, 20-70%, 20-60%, 20-50%, 20-40%, 20-30%, 30-80%, 30-70%, 30-60%, 30-50%, 30-40%, 40-80%, 40-70%, 40-60%, 40-50%, 40-80%, 40-70%, 40-60%, 40-30%, 50-80%, 50-70%, 50-60%, 60-80%, 60-70%, or 70-80% (w / v or v / v). In certain embodiments, the lipid-soluble or hydrophobic component comprises about 10%, about 15%, about 20%, about 25%, about 30%, and about 35% (w / v or v / v) of the nanoparticle composition. In some embodiments, the lipid-soluble or hydrophobic component comprises any combination of percent ranges containing integer values ​​selected from the group consisting of 0-35%, 5-35%, 10-35%, 15-35%, 20-35%, 25-35%, 30-35%, 0-30%, 5-30%, 10-30%, 15-30%, 20-30%, 25-30%, 0-25%, 5-25%, 10-25%, 15-25%, 20-25%, 0-15%, 5-15%, or 10-15% (w / v or v / v) or 10%, 15%, 20%, 25%, 30%, or 35% (w / v or v / v) of the nanoparticle composition. In other embodiments, the upper and / or lower limits of the lipid-soluble or hydrophobic component are determined by any of the recited concentrations described herein. Polar Liquid Carrier

[0081] The polar liquid carrier can be any pharmaceutically acceptable polar liquid capable of forming an emulsion with a lipid. The term "pharmaceutically acceptable" refers to molecular entities and compositions of sufficient purity and quality for use in the formulation of the compositions or pharmaceuticals of the present application, and that do not produce adverse, allergic, or other undesirable reactions when appropriately administered to animals or humans. Both human use (clinical and commercial) and veterinary use are equally encompassed within the scope of the present application, and thus pharmaceutically acceptable formulations include compositions or pharmaceuticals for either human or veterinary use. In one embodiment, the polar liquid carrier is water or a water-based solution. In another embodiment, the polar liquid carrier is a non-aqueous polar liquid such as dimethyl sulfoxide, polyethylene glycol, and polar silicone fluids.

[0082] Water-based solutions generally contain a physiologically compatible electrolyte vehicle that is isotonic or nearly isotonic with whole blood. Carriers can be, for example, saline, saline-glucose mixtures, Ringer's solution, lactated Ringer's solution, Locke-Ringer's solution, Krebs-Ringer's solution, Hartmann's balanced salt solution, heparinized sodium citrate-citric acid-dextrose solution, and polymeric plasma substitutes, such as polyethylene oxide, polyvinylpyrrolidone, polyvinyl alcohol, and ethylene oxide-propylene glycol condensates. The nanoparticle compositions can further contain other components, such as pharmaceutically acceptable carriers, diluents, fillers, and salts, the selection of which will depend on the dosage form utilized, the condition being treated, and the particular objectives to be achieved, as determined by those skilled in the art and the properties of such additives.

[0083] electrolyte In one embodiment, the nanoparticle composition of the present application comprises one or more electrolytes. Electrolytes contemplated for use herein generally include various electrolytes contemplated for medical purposes. Examples of electrolytes include sodium salts (e.g., sodium chloride, sodium bicarbonate, sodium citrate, sodium lactate, sodium sulfate, sodium dihydrogen phosphate, disodium hydrogen phosphate, sodium acetate, sodium glycerophosphate, sodium carbonate, sodium salts of amino acids, sodium propionate, sodium hydroxybutyrate, and sodium gluconate), potassium salts (e.g., potassium chloride, potassium acetate, potassium gluconate, potassium bicarbonate, potassium glycerophosphate, potassium sulfate, potassium lactate, potassium iodide, potassium dihydrogen phosphate, dipotassium hydrogen phosphate, potassium citrate, potassium salts of amino acids, propionate, and sodium gluconate). Examples of suitable salts include potassium phosphate and potassium hydroxybutyrate, calcium salts (e.g., calcium chloride, calcium gluconate, calcium lactate, calcium glycerophosphate, calcium pantothenate and calcium acetate), magnesium salts (e.g., magnesium chloride, magnesium sulfate, magnesium glycerophosphate, magnesium acetate, magnesium lactate and magnesium amino acid salts), ammonium salts (e.g., ammonium chloride), zinc salts (e.g., zinc sulfate, zinc chloride, zinc gluconate, zinc lactate and zinc acetate), iron salts (e.g., ferrous sulfate, ferrous chloride and ferrous gluconate), copper salts (e.g., copper sulfate) and manganese salts (e.g., manganese sulfate). Among these, particularly preferred are sodium chloride, potassium chloride, magnesium chloride, disodium hydrogen phosphate, dipotassium hydrogen phosphate, potassium dihydrogen phosphate, sodium lactate, sodium acetate, sodium citrate, potassium acetate, potassium glycerophosphate, calcium gluconate, calcium chloride, magnesium sulfate and zinc sulfate.

[0084] The concentrations of calcium, sodium, magnesium, or potassium ions are generally within the range of normal physiological concentrations of such ions in plasma. Generally, the desired concentrations of these ions are obtained from dissolved chloride salts of calcium, sodium, and magnesium. Sodium ions can also come from dissolved organic salts of sodium that are also in solution.

[0085] In one embodiment, the electrolyte comprises sodium chloride, sodium lactate, or both.

[0086] In certain embodiments, the nanoparticle composition comprises sodium chloride at a percentage concentration of about 0.2-1%, 0.3-0.9%, 0.4-0.8%, 0.5-0.7%, or about 0.6% (w / v).

[0087] In another embodiment, the nanoparticle composition comprises sodium chloride at a concentration of 50-150 mM, 70-130 mM, 80-120 mM, 90-110 mM, 95-100 mM, or about 97.4 mM.

[0088] In another embodiment, the nanoparticle composition comprises sodium L-lactate, sodium D-lactate, or a mixture thereof at a percent concentration of about 0.1-0.7%, 0.2-0.6%, 0.3-0.5%, 0.35-0.45%, 0.38-0.39%, or about 0.385% (w / v).

[0089] In another embodiment, the nanoparticle composition comprises sodium L-lactate, sodium D-lactate, or a mixture thereof at a concentration of 10-60 mM, 20-50 mM, 30-40 mM, or about 34 mM.

[0090] In one embodiment, the sodium ion concentration is in the range of about 70 to 180 mM, 90 to 170 mM, 70 to 160 mM, 100 to 160 mM, 110 to 150 mM, 120 to 140 mM, 125 to 135 mM, 131 to 133 mM, or about 131.4 mM.

[0091] In one embodiment, the concentration of calcium ions is in the range of about 0.5 to 4.0 mM, 0.5 to 1.0 mM, 0.5 to 2 mM, 0.5 to 3 mM, 1 to 2 mM, 1 to 3 mM, 1 to 4 mM, 2 to 2.5 mM, 2 to 3 mM, 2 to 4 mM, 2.5 to 3 mM, or 3 to 4 mM.

[0092] In one embodiment, the magnesium ion concentration is in the range of 0-10 mM. In another embodiment, the magnesium ion concentration is in the range of about 0.3-0.45 mM, 0.3-0.35 mM, 0.3-0.4 mM, 0.35-0.4 mM, 0.35-0.4 mM, 0.35-0.4 mM, or 0.4-0.45 mM. Because high magnesium ion concentrations negatively affect the intensity of cardiac contractile activity, it is best not to include excessive amounts of magnesium ions in the nanoparticle compositions of the present invention. In a preferred embodiment of the present invention, the nanoparticle compositions contain magnesium ions in an amount below the physiological range.

[0093] In one embodiment, the potassium ion concentration is in the sub-physiological range of 0-5 mEq / L K+ (0-5 mM), preferably 2-3 mEq / L K+ (2-3 mM). Thus, the nanoparticle composition allows for dilution of the potassium ion concentration in stored blood to be transfused. As a result, high potassium ion concentrations and the arrhythmias and heart failure they can cause can be more easily controlled. Nanoparticle compositions containing sub-physiological amounts of potassium are also useful for blood exchange and maintaining a subject's hypothermia.

[0094] In one embodiment, the chloride ion concentration is in the range of 50-200 mM, 50-150 mM, 70-180 mM, 70-130 mM, 80-170 mM, 80-120 mM, 90-160 mM, 90-110 mM, 95-150 mM, 95-100 mM, or about 97.4 mM. In another embodiment, the chloride ion concentration is in the range of 110 mM to 125 mM.

[0095] Other sources of ions include sodium salts (e.g., sodium bicarbonate, sodium citrate, sodium lactate, sodium sulfate, sodium dihydrogen phosphate, disodium hydrogen phosphate, sodium acetate, sodium glycerophosphate, sodium carbonate, sodium salts of amino acids, sodium propionate, sodium 3-hydroxybutyrate, and sodium gluconate), potassium salts (e.g., potassium acetate, potassium gluconate, potassium bicarbonate, potassium glycerophosphate, potassium sulfate, potassium lactate, potassium iodide, potassium dihydrogen phosphate, dipotassium hydrogen phosphate, potassium citrate, amino acids, Examples of suitable salts include potassium salts, potassium propionate, and potassium 3-hydroxybutyrate), calcium salts (e.g., calcium gluconate, calcium lactate, calcium glycerophosphate, calcium pantothenate, and calcium acetate), magnesium salts (e.g., magnesium sulfate, magnesium glycerophosphate, magnesium acetate, magnesium lactate, and magnesium amino acid salts), ammonium salts, zinc salts (e.g., zinc sulfate, zinc chloride, zinc gluconate, zinc lactate, and zinc acetate), iron salts (e.g., ferrous sulfate, ferrous chloride, and ferrous gluconate), copper salts (e.g., copper sulfate), and manganese salts (e.g., manganese sulfate). Among these, particularly preferred are sodium chloride, potassium chloride, magnesium chloride, disodium hydrogen phosphate, dipotassium hydrogen phosphate, potassium dihydrogen phosphate, sodium lactate, sodium acetate, sodium citrate, potassium acetate, potassium glycerophosphate, calcium gluconate, calcium chloride, magnesium sulfate, choline chloride, and zinc sulfate.

[0096] Gas-holding capacity of nanoparticle compositions Lipid-soluble or hydrophobic components in nanoparticle compositions in the form of micelles and / or red blood cell ghosts, etc., provide the nanoparticle composition with the ability to retain larger amounts of lipid-soluble gases than a completely aqueous solution, specifically, to dissolve the lipid-soluble gases in the lipid-soluble portion of the nanoparticle composition to form a homogeneous solution with the lipid-soluble or hydrophobic components and any other hydrophobic liquid substances that may be present in the lipid-soluble or hydrophobic portion of the nanoparticle composition.

[0097] In one embodiment, the lipid-soluble gas is oxygen. Oxygen is 4.41 times more soluble in lipids than in water (Battion et al., J. Amer. Oil Chem. Soc. 1968, 45:830-833). Therefore, nanoparticle compositions with a higher lipid content can retain more oxygen than nanoparticle compositions with a lower lipid content. In one embodiment, the nanoparticle composition has a lipid content of about 1-80% (w / v). In other embodiments, the nanoparticle composition has a lipid content of about 10-80% (w / v), 20-60% (w / v), about 20-50% (w / v), about 20-40% (w / v), or about 20-25% (w / v). In yet another embodiment, the nanoparticle composition has a lipid content of about 21.8%. In certain embodiments, the nanoparticle composition is prepared by mixing a lipid-soluble or hydrophobic component and a polar liquid component in the presence of normal air. In other embodiments, the nanoparticle composition is further oxygenated by bubbling normal air or pure oxygen through the nanoparticle composition for a desired period of time. Because bubbles are undesirable during circulation due to the possibility of air embolism, a bubble trap must be added to remove bubbles, leaving only the gas dissolved in the core of the micelles, in the polar carrier, or attached to the protein or other additives. Gas can also be loaded onto the micelles by equilibrating the micelles with gas-enriched air combined with gentle movement of the nanoparticle composition in a mixing chamber to avoid bubble formation. Loading can also be performed under pressures greater than 1 atmosphere, followed by releasing the pressure to release excess gas.

[0098] In another embodiment, the lipid soluble gas is xenon (Xe) or argon (Ar). In another embodiment, the lipid soluble gas is nitric oxide (NO). In another embodiment, the lipid soluble gas is hydrogen sulfide (HS). In yet another embodiment, the lipid soluble gas is carbon monoxide (CO).

[0099] In one embodiment, the nanoparticle composition contains micelles loaded with a gas mixture (e.g., a mixture of oxygen, hydrogen sulfide, carbon monoxide, and / or nitric oxide). In another embodiment, the nanoparticle composition contains a mixture of micelles loaded with different gases. For example, a mixture of micelles can contain 50% NO-loaded micelles and 50% O-loaded micelles.

[0100] Rigid non-planar molecules The nanoparticle compositions may further comprise molecules with rigid, non-planar structures that create greater disorder and greater interstitial space for gas molecules in the hydrophobic core of the micellar structure, thereby adjusting the gas-holding capacity of the micelles. Examples of such molecules include, but are not limited to, (+) naloxone, (+) morphine, and (+) naltrexone.

[0101] In one embodiment, the molecule having a rigid, non-planar structure is (+) naloxone, which, unlike the opiate receptor antagonist (-) naloxone, does not bind to opiate receptors and does not increase pain like (-) naloxone. In another embodiment, (+) naloxone is -5 ~10 -4 In another embodiment, (+) naloxone is used at a concentration of 10 -4 It is used at concentrations of M or higher.

[0102] In one embodiment, (+) naloxone is 10 -5 ~10 -4 It is used in a concentration range that produces an anti-inflammatory effect in M.

[0103] Molecules with non-planar structures also include organic molecules with branched structures, examples of which include, but are not limited to, tri-n-octylamine, tri-n-hexylamine, boric acid, tris(3,5-dimethyl-4-heptyl) ester, metal-complexed and non-metal-complexed deuteroporphyrin dimethyl ester and their derivatives, hexaphenylsilole, and silicone polymers.

[0104] plasma components The nanoparticle composition may further comprise a plasma component. In one embodiment, the plasma is animal plasma. In another embodiment, the plasma is human plasma. Without wishing to be bound by any particular scientific theory, it is believed that intravascular administration of a liquid may dilute the concentration of clotting factors to undesirable levels. Therefore, using plasma as a diluent for oxygen-carrying components avoids this problem. Plasma may be collected by any means known in the art, provided that red blood cells, white blood cells, and platelets are essentially removed. Preferably, the plasma is obtained using an automated plasmapheresis device. Plasmapheresis devices are commercially available and include devices that separate plasma from blood by, for example, ultrafiltration or centrifugation. Ultrafiltration-based plasmapheresis devices, such as those manufactured by Auto C, A200 (Baxter International Inc., Deerfield, IL), are suitable because they effectively remove red blood cells, white blood cells, and platelets while preserving clotting factors.

[0105] Plasma can be collected using an anticoagulant, many of which are known in the art. Preferred anticoagulants are those that chelate calcium, such as citrate. In one embodiment, sodium citrate is used as the anticoagulant at a final concentration of 0.2-0.5%, preferably 0.3-0.4%, and most preferably 0.38%. The plasma can be fresh, frozen, pooled, and / or sterilized. While plasma from an external source may be preferred, it is within the scope of the present application to use autologous plasma collected from the subject prior to formulation and administration of the nanoparticle composition.

[0106] In addition to plasma from natural sources, synthetic plasma can also be used. The term "synthetic plasma" as used herein refers to any aqueous solution containing at least one plasma protein. Proteins similar to plasma proteins can also be used.

[0107] Oncotic agents In one embodiment, the nanoparticle composition further comprises an oncotic agent in addition to the nanoparticles (micelles or liposomes), which are composed of molecules that are sufficiently large to prevent their loss from the circulation by crossing fenestrations in capillary beds into the interstitial spaces of body tissues. Examples of oncotic agents include, but are not limited to, dextran (e.g., low-molecular-weight dextran), dextran derivatives (e.g., carboxymethyldextran, carboxydextran, cationic dextran, and dextran sulfate), hydroxyethyl starch, hydroxypropyl starch, branched, unsubstituted, or substituted starch, gelatin (e.g., modified gelatin), albumin (e.g., human plasma, human serum albumin, heated human plasma protein, and recombinant human serum albumin), PEG, polyvinylpyrrolidone, carboxymethylcellulose, acacia gum, glucose, dextrose (e.g., glucose monohydrate), oligosaccharides (e.g., oligosaccharides), polysaccharide degradation products, amino acids, and protein degradation products. Among these, particularly preferred are low-molecular-weight dextran, hydroxyethyl starch, modified gelatin, and recombinant albumin.

[0108] Albumin, due to its antioxidant effect, may also be used to minimize reactive oxygen species interactions with the micelle components and stabilize the micelle structure. In one embodiment, the oncotic agent is about 2%, 5%, 7%, or 10% (w / v) albumin. In another embodiment, the oncotic agent is a polysaccharide, such as a dextran in the molecular weight range of 30,000 to 50,000 Daltons (D). In yet another embodiment, the oncotic agent is a polysaccharide, such as a dextran in the molecular weight range of 50,000 to 70,000 D. High molecular weight dextran solutions are more effective in preventing tissue swelling due to their lower capillary leakage rate.

[0109] In one embodiment, the concentration of polysaccharide is sufficient to achieve an osmolality of about 28 mmHg (when utilized together with chloride salts of sodium, calcium, and magnesium, organic ions from organic salts of sodium, and the hexose sugars discussed above), approximating the osmolality of normal human serum.

[0110] In another embodiment, the oncotic agent is glycerol or mannitol in an amount of about 2%, 2.5%, 3%, 3.5%, 4%, 4.5%, 5%, 10%, 15%, 20%, 25%, or 30% (w / v) of the nanoparticle composition, hi other embodiments, the nanoparticle composition comprises glycerol or mannitol in an amount of 2-5% w / v.

[0111] Crystalloids The nanoparticle composition may also include a crystalloid. The crystalloid may be any crystalloid capable of achieving an osmolality of preferably greater than 800 mOsm / L in the nanoparticle composition, i.e., making the nanoparticle composition "hypertonic." Examples of suitable crystalloids and their concentrations in the nanoparticle composition include, but are not limited to, 3% w / v NaCl, 7% NaCl, 7.5% NaCl, and 7.5% NaCl in 6% w / v dextran. In one embodiment, the nanoparticle composition has an osmolality of 800-2400 mOsm / L.

[0112] Anti-inflammatory and immunomodulatory drugs In one embodiment, the nanoparticle composition of the present application further comprises an anti-inflammatory or immunomodulatory agent. Examples of anti-inflammatory agents that have been shown to inhibit reactive oxygen species include, but are not limited to, histidine, albumin, (+) naloxone, prostaglandin D2, and molecules of the phenylalkylamine class. Other anti-inflammatory compounds and immunomodulatory agents include interferons; interferon derivatives including betaseron and beta-interferon; prostane derivatives including iloprost and cicaprost; glucocorticoids including cortisol, prednisolone, methyl-prednisolone, and dexamethasone; immunosuppressants including cyclosporin A, methoxsalen, sulfasalazine, azathioprine, and methotrexate; lipoxygenase inhibitors including zileuton, MK-886, WY-50295, SC-45662, SC-41661A, and BI-L-357; leukotriene antagonists; peptide derivatives including ACTH and its analogs; soluble TNF-receptors; anti-TNF antibodies; soluble receptors for interleukins or other cytokines; antibodies against receptors for interleukins or other cytokines, T-cell proteins; and calcipotriol and its analogs, used alone or in combination.

[0113] Carbohydrates and amino acids The nanoparticle composition may contain a carbohydrate or mixture of carbohydrates. Suitable carbohydrates include, but are not limited to, simple hexoses (e.g., glucose, fructose, and galactose), mannitol, sorbitol, or others known to those skilled in the art. In one embodiment, the nanoparticle composition contains physiological levels of hexoses. "Physiological levels of hexoses" includes hexose concentrations between 2 mM and 50 mM. In one embodiment, the nanoparticle composition contains 5 mM glucose. Sometimes, it is desirable to increase the hexose concentration to provide nutrients to cells. Thus, the hexose range can be extended up to about 50 mM if necessary to provide minimal calories for nutrition.

[0114] Other suitable carbohydrates include various sugars that are intended to be used for medical purposes, such as xylitol, dextrin, glycerin, sucrose, trehalose, glycerol, maltose, lactose, and erythritol.

[0115] The nanoparticle composition may contain one or more amino acids and / or one or more oligopeptides. Suitable amino acids include, but are not limited to, alanine, arginine, aspartate, asparagine, cysteine, glutamate, glutamine, glycine, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, proline, serine, threonine, tryptophan, tyrosine, threonine, tryptophan, valine, and 2-aminopentaenoic acid. In one embodiment, the amino acid is selected from the group consisting of histidine, tyrosine, phenylalanine, and cysteine. In another embodiment, the nanoparticle composition contains one or more amino acids known to prevent apoptosis. Examples of such amino acids include glutamine, glycine, proline, and 2-aminopentaenoic acid.

[0116] Amino acids may be used at concentrations ranging from 0.1 fM to 200 mM, 0.1 fM to 100 pM, 100 pM to 10 nM, 10 nM to 10 μM, 0.01 to 200 mM, 0.2 to 50 mM, or 0.5 to 2 mM. In one embodiment, amino acids are used at a concentration of 1 mM.

[0117] buffer The nanoparticle composition of the present application may further comprise a biological buffer to maintain the pH of the liquid in the physiological range of pH 7 to 8. Examples of biological buffers include, but are not limited to, N-2-hydroxyethylpiperazine-N'-2-hydroxypropanesulfonic acid (HEPES), 3-(N-morpholino)propanesulfonic acid (MOPS), 2-([2-hydroxy-1,1-bis(hydroxymethyl)ethyl]amino)glyci ethanesulfonic acid (TES), 3-[N-tris(hydroxymethyl)methylamino]-2-hydroxyethyl]-1-piperazinepropanesulfonic acid (EPPS), Tris[hydrolymethyl]aminoethane (THAM), and Tris[hydroxylmethyl]methylaminomethane (TRIS).

[0118] In one embodiment, the buffering agent is a histidine, imidazole, substituted histidine, or imidazole compound that retains the amphiphilic moiety of an imidazole ring, a histidine- or glycine-containing oligopeptide (e.g., glygly), or a mixture thereof. Histidine can also reduce reactive oxygen species and inhibit cell contraction. (See, e.g., Simpkins et al., J. Trauma. 2007, 63:565-572.) Histidine or imidazole can be used at a concentration of about 1 mM, 5 mM, 10 mM, 20 mM, 30 mM, 40 mM, or 50 mM, or at a concentration range of about 0.1 mM to about 200 mM, 1 mM to about 100 mM, 5 mM to about 50 mM, or 5 mM to about 20 mM, or any other range between any of the histidine concentrations listed herein.

[0119] In another embodiment, the nanoparticle compositions herein utilize common biological components to maintain biological pH in vivo. Briefly, some biological compounds, such as lactate, are metabolizable in vivo and work with other biological components to maintain a biologically appropriate pH in animals. The biological components are effective in maintaining a biologically appropriate pH, even at low temperatures and in essentially bloodless conditions. Examples of common biological components include, but are not limited to, carboxylic acids, their salts, and esters. Carboxylic acids have the general structural formula RCOOX, where R is alkyl, alkenyl, or aryl, branched or straight-chain, containing 1 to 30 carbons, which may be substituted, and X is hydrogen or sodium or other biologically compatible ionic substituent that may be attached at the oxygen position, or a short straight- or branched-chain alkyl containing 1 to 4 carbons, e.g., --CH3, --CH2CH3. Examples of carboxylic acids and carboxylates include, but are not limited to, lactic acid and sodium lactate, citric acid and sodium citrate, gluconic acid and sodium gluconate, pyruvic acid and sodium pyruvate, succinic acid and sodium succinate, and acetic acid and sodium acetate.

[0120] Coagulation promoters In certain embodiments, the nanoparticle composition may further comprise one or more coagulation promoters. Examples of coagulation factors include, but are not limited to, factor VII, thrombin, platelets, and tranexemic acid. These factors may be derived from natural or non-natural sources. In certain embodiments, factor VII is added to the nanoparticle composition at a concentration of 70-150 IU / kg, prothrombin complex is added to the nanoparticle composition at a concentration of 15-40 IU / kg, and fibrinogen is added to the nanoparticle composition at a concentration of 50-90 mg / kg. Naturally derived or synthetic platelets or platelet substitutes may also be added.

[0121] antioxidants In certain embodiments, the nanoparticle compositions may further comprise one or more antioxidants. Examples of antioxidants include sodium bisulfite, sodium sulfite, sodium pyrosulfite (e.g., sodium metabisulfite), Rongalite (CH2OHSO2Na), ascorbic acid, sodium ascorbate, erythorbic acid, sodium erythorbate, cysteine, cysteine ​​hydrochloride, homocysteine, glutathione, thioglycerol, α-thioglycerin, sodium edetate, citric acid, isopropyl citrate, potassium dichloroisocyanurate, sodium thioglycolate, sodium pyrosulfite 1,3-butylene glycol, calcium disodium ethylenediaminetetraacetate, disodium ethylenediaminetetraacetate, amino acid sulfites (e.g., sulfites). Examples of suitable antioxidants include, but are not limited to, sodium bisulfite, sodium sulfite, ascorbic acid, propyl gallate, ascorbyl palmitate, vitamin E and its derivatives (e.g., dl-α-tocopherol, tocopherol acetate, natural vitamin E, d-δ-tocopherol, mixed tocopherols, and Trolox), guaiac, nordihydroguaiaretic acid (NDGA), L-ascorbic acid stearate, soy lecithin, ascorbic acid palmitate, benzotriazole, and pentaerythrityl-tetrakis[3-(3,5-di-t-butyl-4-hydroxyphenyl)propionate]2-mercaptobenzimidazole. Among these, sodium bisulfite, sodium sulfite, ascorbic acid, homocysteine, dl-α-tocopherol, tocopherol acetate, glutathione, and Trolox are preferred.

[0122] Other components In addition to the components discussed above, the nanoparticle compositions may contain antibiotics such as penicillin, cloxacillin, dicloxacillin, cephalosporins, erythromycin, amoxicillin-clavulanate, ampicillin, tetracycline, trimethoprim-sulfamethoxazole, chloramphenicol, ciprofloxacin, aminoglycosides (e.g., tobramycin and gentamicin), streptomycin, sulfa drugs, kanamycin, neomycin, randomonobactam, and the like; antivirals such as amantadine hydrochloride, rimantadine, acyclovir, famciclovir, foscarnet, ganciclovir sodium, idoxuridine, ribavirin, sorivudine, trifluridine, and the like; , valacyclovir, valganciclovir, penciclovir, vidarabine, didanosine, stavudine, zalcitabine, zidovudine, interferon alpha, and edoxudine; antifungal agents such as terbinafine hydrochloride, nystatin, amphotericin B, griseofulvin, ketoconazole, miconazole nitrate, flucytosine, fluconazole, itraconazole, clotrimazole, benzoic acid, salicylic acid, voriconazole, caspofungin, and selenium sulfide; vitamins, amino acids, vasodilators such as alcohols and polyalcohols, surfactants, antibodies against harmful cytokines such as tumor necrosis factor (TNF) or interleukins, and mediators of vascular potency and immunomodulators such as prostaglandins, leukotrienes, pro-opiomelanocortin fragments, and platelet-activating factor.

[0123] In certain embodiments, the nanoparticle compositions may further contain beneficial anions, such as lactate or glutamate ions. Hypertonic lactate-containing compositions have been shown to be effective in reducing cerebral edema in patients with acute hemodynamic distress. In one embodiment, the nanoparticle composition contains 250-2400 mM lactate or lactate salts. In another embodiment, the nanoparticle composition contains 250-2400 mM lactate or lactate salts and 2-10 mM potassium.

[0124] In certain other embodiments, the nanoparticle composition can contain a substituting cation, for example, the nanoparticle composition can contain choline to substitute for sodium ions.

[0125] In some other embodiments, the nanoparticle composition further comprises a potassium channel blocker, which can inhibit programmed cell death by preventing potassium excretion.

[0126] In certain embodiments, the nanoparticle compositions further comprise an anti-cancer drug and / or an intracellular signaling molecule, such as Camp and diacylglycerol. In other embodiments, the nanoparticle compositions further comprise one or more organelles or organelle components, such as, in whole or in part, the endoplasmic reticulum, ribosomes, and mitochondria.

[0127] In other embodiments, the nanoparticle compositions may be combined with red blood cells, modified red blood cells, or other cellular components of blood.

[0128] In yet other embodiments, the nanoparticle compositions further comprise proopiomelanocortin fragments, such as β-endorphin and melanocyte-stimulating hormone, enkephalins, or opiates, to modify immune responses and provide analgesia. β-endorphin may also be used at final concentrations of 0.01-100 nm, preferably 0.1-10 nm, and more preferably about 1 nm, to modulate neutrophil function in septic conditions.

[0129] In yet other embodiments, the nanoparticle composition further comprises one or more neurotropic agents for the treatment of psychiatric disorders or the prevention of psychiatric disorders.

[0130] IV. Preparation of Nanoparticle Compositions The nanoparticle composition can be prepared by mixing a lipophilic or hydrophobic component, an emulsifier, an aqueous carrier, and any other components to form an emulsion. Commonly used mixing methods include, but are not limited to, stirring, shaking, homogenizing, vibrating, microfluidizing, and sonication.

[0131] A typical homogenizer is the APV2000 homogenizer (SPX Corporation). Emulsions can be formed at pressure settings of about 15,000-20,000 psi for nanoemulsions <100 nm or about 22,000-28,000 psi for larger micellar emulsions of about 300 nm. Multiple homogenization cycles may be required to produce micelles of the desired size. The number of homogenization cycles may vary depending on the formulation; for example, 6, 8, 10, 12, or 15 cycles may be required.

[0132] Suitable particle analyzers and / or zeta potential analyzers can be used to assess and monitor the size and stability of micelle compositions. Exemplary analyzers include the Malvern Zetasizer Nano ZS, which can provide both size and zeta potential measurements.

[0133] In one embodiment, the nanoparticle composition is formed by mixing an aqueous carrier with a lipid emulsion preformed from the above components. Furthermore, the nanoparticle composition can be retained in red blood cell ghosts. Specifically, the emulsion should be prepared to allow the lipid-soluble gas to dissolve in the lipid-soluble or hydrophobic portion of the emulsion but not form tiny bubbles that could increase the risk of gas embolism.

[0134] In certain embodiments, albumin or albumin polymers or albumin polymers conjugated to amino acids or peptides are added to the nanoparticle compositions in amounts of 2-40% (w / v), about 2-20% (w / v), about 4-10% (w / v), or about 5% (w / v). Albumin or albumin polymers or albumin polymers conjugated to amino acids or peptides are added to the nanoparticle compositions after micelle formation. In one embodiment, a lipid-soluble or hydrophobic component, an emulsifier, an aqueous carrier, and any other non-albumin components are mixed to form an emulsion. Albumin, albumin polymers, or albumin polymers conjugated to amino acids or peptides are then dissolved in the emulsion at the desired concentration.

[0135] In some embodiments, Part A or a mixture of Parts A and B is loaded with oxygen, nitric oxide, carbon monoxide, xenon, argon, hydrogen sulfide, or other hydrophobic gases, or mixtures of these gases, prior to use. These gases can be used to deliver oxygen for aerobic metabolism after the initial bolus, provide an initial carbon monoxide bolus to protect against MODS, and open blood vessels in vascular diseases or conditions involving vasoconstriction or blockage; xenon or argon can be used to protect against the effects of traumatic brain injury or epileptic seizures; or hydrogen sulfide can be used to promote long-term tissue preservation. Nitric oxide-loaded micelles can also be used as an antihypertensive agent. Either Part A, Part B, or a mixture of Parts A and B can be sterilized by autoclaving.

[0136] In some embodiments, soybean oil, which promotes clotting, is replaced with chia bean oil, which is anti-inflammatory and reduces clotting. In one embodiment, the soybean oil-containing nanoparticle composition is used in the early stages of the infusion when bleeding is occurring. The chia bean oil-containing nanoparticle composition is used in the later stages of the infusion when bleeding is no longer an issue.

[0137] In some other embodiments, glycerol in Part A is replaced with mannitol. In other embodiments, egg phospholipids are replaced with α-phosphatidylcholine to eliminate a potential source of protein contamination and anaphylaxis (due to contamination of egg phospholipids with egg proteins). In still other embodiments, amino acids in Part B of Recipe 2 are replaced with N-acetyl amino acids. In one embodiment, the nanopartic nanoparticle composition is a non-oxygenated nanoparticle composition. As used herein, the term "non-oxygenated nanoparticle composition" refers to a formulation prepared in air and not loaded with oxygen by any oxygenation device or method.

[0138] In some embodiments, the nanoparticle composition comprises an amphiphilic emulsifier in an amount of 6% to 18% (w / v); a lipophilic or hydrophobic component in an amount of 15 to 35% (w / v); a polar liquid carrier; and one or more electrolytes, wherein the amphiphilic emulsifier forms lipid-loaded micelles (LM) having a lipophilic or hydrophobic core containing the lipophilic or hydrophobic component in the polar liquid carrier, and the diameter of the LM is in the range of 20 to 140 nm. In some further embodiments, the nanoparticle compositions have diameters in the range of 30-140 nm, 30-130 nm, 30-120 nm, 30-100 nm, 30-90 nm, 30-80 nm, 30-70 nm, 40-140 nm, 40-130 nm, 40-120 nm, 40-100 nm, 40-90 nm, 40-80 nm, 50-140 nm, 50-130 nm, 50-120 nm, 50-100 nm, 50-160 nm, 50-200 nm, 50-220 nm, 50-300 nm, 50-320 nm, 50-400 nm, 50-500 nm, 50-600 nm, 50-700 nm, 50-800 nm, 50-900 nm, 50-800 nm, 50-1400 nm, 50-130 nm, 50-120 nm, 50-100 nm, 50-1600 nm, 50-2200 nm, 50-3200 nm, 50-400 nm, 50-500 nm, 50-600 nm, 50-700 nm, 50-800 nm, 50-9 ... This includes LMs that are up to 90nm, 50 to 80nm, 50 to 70nm, 60 to 140nm, 60 to 130nm, 60 to 120nm, 60 to 100nm, 60 to 90nm, 60 to 80nm, 80 to 140nm, 80 to 130nm, 80 to 120nm, 80 to 110nm, 80 to 100nm, 100 to 140nm, 100 to 130nm, 100 to 120nm, 100 to 110nm, 120 to 140nm, 120 to 130nm or 130 to 140nm.

[0139] In some further embodiments, the nanoparticle composition further comprises liposomes having a diameter in the range of 1-30 nm, 1-25 nm, 1-20 nm, 1-15 nm, 1-10 nm, 3-30 nm, 3-25 nm, 3-20 nm, 3-15 nm, 3-10 nm, 5-30 nm, 5-25 nm, 5-20 nm, 5-15 nm, 5-10 nm, 7-30 nm, 7-25 nm, 7-20 nm, 7-15 nm, 7-10 nm, 10-30 nm, 10-25 nm, 10-20 nm, 10-15 nm, 15-30 nm, 15-25 nm, 15-20 nm, 20-30 nm, 20-25 nm, or 25-30 nm, as measured by electron microscopy.

[0140] In some further embodiments, the nanoparticle composition comprises nanoparticles (including micelles and liposomes) having an average diameter in the range of about 70-160 nm, 70-150 nm, 70-140 nm, 70-130 nm, 70-120 nm, 70-100 nm, 70-90 nm, 80-160 nm, 80-150 nm, 80-140 nm, 80-130 nm, 80-120 nm, 80-100 nm, 80-90 nm, 90-160 nm, 90-150 nm, 90-140 nm, 90-130 nm, 90-120 nm, 90-100 nm, 90-98 nm, 92-96 nm, or 95-100 nm, as measured by light scattering.

[0141] In some embodiments, the nanoparticle composition comprises a mixture of LMs with diameters ranging from 30 to 500 nm and liposomes with diameters ranging from 1 to 30 nm, as measured by electron microscopy.

[0142] In some embodiments, the nanoparticle composition comprises a mixture of LMs and liposomes, and the mean diameter of all particles ranges from 5-25 nm, 5-20 nm, 5-15 nm, 5-10 nm, 10-25 nm, 10-20 nm, 10-15 nm, 15-25 nm, 15-20 nm, or 20-25 nm, as determined by electron microscopy.

[0143] In some embodiments, the nanoparticle composition comprises about 12% egg lecithin and comprises LMs with diameters of about 30-500 nm and liposomes with diameters of about 1-25 nm as determined by electron microscopy. In some embodiments, the nanoparticle composition comprises about 12% egg lecithin and comprises LMs with diameters of about 40-100 nm and liposomes with diameters of about 7-20 nm as determined by electron microscopy.

[0144] In some embodiments, the nanoparticle composition comprises about 5-35% soybean oil and 0.5-20% egg lecithin, and comprises LMs with diameters of about 15-800 nm and liposomes with diameters of about 1-300 nm, as determined by electron microscopy.

[0145] In some embodiments, the nanoparticle composition comprises about 5-25% soybean oil and 0.5-1.5% egg lecithin, and comprises LMs with diameters of about 30-400 nm and liposomes with diameters of about 1-150 nm, as determined by electron microscopy.

[0146] In some embodiments, the nanoparticle composition comprises about 5-25% soybean oil and 0.5-1.5% egg lecithin, and comprises LMs with diameters of about 30-400 nm and liposomes with diameters of about 1-150 nm, as determined by electron microscopy.

[0147] In some embodiments, the nanoparticle composition comprises about 12% egg lecithin and comprises LMs with diameters of about 40-100 nm and liposomes with diameters of about 7-20 nm as determined by electron microscopy.

[0148] In some embodiments, the nanoparticle composition further comprises glycerin in an amount of 1-10%, 1-8%, 1-5%, 1-3%, 1-2%, 5-10%, 2-8%, 2-5%, 2-3%, 3-10%, 3-8%, 3-5%, 5-10%, 5-8%, or 8-10% (w / v).

[0149] In some embodiments, the nanoparticle composition further comprises NaCl at a final concentration of 50-200 mM, 50-150 mM, or 50-100 mM.

[0150] In some embodiments, the nanoparticle compositions are prepared under atmospheric conditions without enrichment of oxygen, carbon monoxide, nitric oxide, or xenon.

[0151] In certain embodiments, the nanoparticle composition can be loaded with a lipid-soluble gas prior to clinical application. Examples of such gases include, but are not limited to, oxygen, xenon, argon, nitric oxide, carbon monoxide, and hydrogen sulfide. The gas is present in an amount sufficient to regulate vascular function and cellular nanoparticle bolism. As used herein, a "lipid-soluble gas-loaded nanoparticle composition" refers to a composition that has been subjected to a process to increase the content of such lipid-soluble gas in the nanoparticle composition. The nanoparticle composition can be loaded with a lipid-soluble gas by bubbling the lipid-soluble gas through the nanoparticle composition for a desired period of time or by stirring the nanoparticle composition in the presence of the lipid-soluble gas under pressure.

[0152] In one embodiment, the nanoparticle composition is oxygenated by bubbling pure oxygen or a gas having an oxygen content ranging from 21% to 100% (v / v), preferably 40% to 100% (v / v), more preferably 60% to 100% (v / v), and most preferably 80% to 100% (v / v), through the mixture for 30 seconds or more, preferably 1 to 15 minutes, more preferably 1 to 5 minutes. Oxygen can also be added under pressure, followed by a reduction in pressure to 1 atmosphere. In one embodiment, the nanoparticle composition is oxygenated immediately before administration. The nanoparticle composition can be oxygenated using a portable oxygen tank or a portable oxygen concentrator, such as the Evergo Portable Pulse Dose oxygen concentrator manufactured by Philips Healthcare of Andover, MA.

[0153] Another method is to allow the emulsion to equilibrate with the gas-filled atmosphere to be added. In most cases, a bubble trap is required to remove bubbles that can cause gas embolism. The equilibration time for a particular nanoparticle composition can be determined experimentally.

[0154] In some embodiments, the nanoparticle composition comprises an oxygenated lipid emulsion. As used herein, the term "oxygenated lipid emulsion" or "oxygenated nanoparticle composition" refers to a particular type of gassed lipid emulsion or gassed fluid that is forced to absorb oxygen such that the total concentration of oxygen contained therein is higher than the concentration present in the same liquid at atmospheric equilibrium.

[0155] Example The following examples are presented to provide those of ordinary skill in the art with a complete disclosure and description of how to practice the methods of the present application, and are not intended to limit the scope of the present invention. Efforts have been made to ensure accuracy with respect to numbers used (e.g., amounts, temperatures, etc.), but some experimental error and deviation should be accounted for. Unless otherwise indicated, parts are parts by weight, molecular weight is weight average molecular weight, temperature is in degrees Celsius, and pressure is at or near atmospheric.

[0156] Example 1: Preparation of Nanoparticle Composition No. 1 Preparation of Part A Soybean oil 20% = 20g / 100ml Egg yolk phospholipids 1.2g / 100ml The nanoparticle composition is produced by sonication or microfluidization and / or homogenization. Preparation of Part B Glycerol 2.25% NaCl 77mM

[0157] Example 2: Preparation of Nanoparticle Composition No. 2 Preparation of Part A Soybean oil 10%~20% = 10~20g / 100ml Egg yolk phospholipids 0.6%~12% = 0.6~12 grams The nanoparticle composition is produced by sonication or microfluidization and / or homogenization. Preparation of Part B Glycerol 2.25% NaCl 77mM

[0158] Example 3: Preparation of Nanoparticle Composition No. 3 Preparation of Part A Soybean oil 10%~20% = 10~20 grams Egg yolk phospholipids 0.6%~12% = 0.6~12 grams The nanoparticle composition is produced by sonication or microfluidization and / or homogenization. Preparation of Part B Glycerol 2.25% NaCl 77mM L-histidine 1mM

[0159] Example 4: Preparation of Nanoparticle Composition No. 4 Preparation of Part A Egg yolk phospholipids 0.6%~12% = 0.6~12 grams The nanoparticle composition is produced by sonication or microfluidization and / or homogenization. Preparation of Part B Glycerol 2.25% NaCl 77mM

[0160] Example 5: Preparation of Nanoparticle Composition No. 5 Preparation of Part A Egg yolk phospholipids 0.6%~12% = 0.6~12 grams The nanoparticle composition is produced by sonication or microfluidization and / or homogenization. Preparation of Part B Glycerol 2.25% NaCl 77mM L-histidine 1mM

[0161] Example 6: Preparation of Nanoparticle Composition No. 6 Preparation of Part A Soybean oil 10%~20% = 10~20 grams Egg yolk phospholipids 0.6%~12% = 0.6~12 grams The nanoparticle composition is produced by sonication or microfluidization and / or homogenization. Preparation of Part B Glycerol 2.25% NaCl 77mM L-histidine 77mM Albumin 5% (w / v)

[0162] Example 7: Preparation of Nanoparticle Composition No. 7 Preparation of Part A Soybean oil 10%~20% = 10~20 grams Egg yolk phospholipids 0.6%~12% = 0.6~12 grams The nanoparticle composition is produced by sonication or microfluidization and / or homogenization. Preparation of Part B NaCl 103mM L-lactate Na 34mM L-histidine 1mM

[0163] Part A can be used alone or mixed with Part B within 24 hours of use or can be premixed. Either or both parts can be lyophilized and water can be added at the time of use. In some embodiments, glycerin was added to the final product at a final concentration of 1.13% (w / v) or 2.25% (w / v).

[0164] Example 7: Treatment of hyperprocalcitonemia with the nanoparticle compositions of the present application Septic patients with hyperprocalcitonemia were treated with nanoparticle composition No. 1, described in Example 1. Treatment with the nanoparticle composition consistently reduced procalcitonin levels in the bloodstream and improved the function of multiple organs. Blood procalcitonin levels were measured before treatment with the nanoparticle composition, followed by subsequent measurements over the next 48 hours. The results are shown in Table 1 below. [Table 1]

[0165] These data show that there was a very significant decrease in procalcitonin within 48 hours after infusion of the VBI-S nanoparticle composition. This decrease was not simply due to patient improvement, as there was still a decrease in procalcitonin in patients 01-012-002, 01-012-005, and 01-006-003, who did not survive the 48-hour treatment period. The decrease was not due to dilution, as sodium and blood urea nitrogen concentrations did not change and the average volume of nanoparticle composition administered was only 632 ml.

[0166] This reduction in procalcitonin by the nanoparticle compositions of the present application was unexpected because injection of liposome compositions has been shown to increase blood levels of inflammatory mediators, such as tumor necrosis factor and interleukin 6, which are known to increase procalcitonin. Thus, one skilled in the art would expect injection of the nanoparticle compositions of the present application to lead to an increase in procalcitonin, and the inventors have observed a definite and consistent reduction.

[0167] The terms and descriptions used herein are set forth by way of example only and are not meant to be limiting. Those skilled in the art will recognize that many variations are possible within the spirit and scope of the invention as defined in the following claims and their equivalents, and that all terms are to be understood in their broadest possible sense unless otherwise specified.

Claims

1. 1. A method for treating hyperprocalcitoninemia in a subject, comprising: For subjects requiring treatment, an amphiphilic emulsifier in an amount of 0.1% to 100% (w / v); a fat-soluble or hydrophobic component in an amount of 0-35% (w / v); a polar liquid carrier; one or more electrolytes; administering an effective amount of a nanoparticle composition comprising: The method, wherein the nanoparticle composition comprises liposomes and / or micelles having diameters in the range of 1 to 800 nm.

2. 10. The method of claim 1, wherein the fat-soluble or hydrophobic component is selected from the group consisting of soybean oil, chia bean oil, and algae oil.

3. 3. The method of claim 1, wherein the amphiphilic emulsifier is selected from the group consisting of phospholipids, α-phosphatidylcholines, amphiphilic peptides and amphiphilic polymers.

4. 4. The method according to claim 1, wherein the amphiphilic emulsifier is selected from the group consisting of egg yolk lecithin and soybean lecithin.

5. 5. The method of any one of claims 1 to 4, wherein the polar liquid carrier is selected from the group consisting of water, water-based solutions, and non-aqueous polar liquids.

6. 6. The method of any one of claims 1 to 5, wherein the non-aqueous polar liquid is selected from the group consisting of dimethyl sulfoxide, polyethylene glycol and polar silicone fluids.

7. 7. The method of claim 1, wherein the electrolyte is selected from the group consisting of one or more of sodium chloride, sodium bicarbonate, sodium citrate, sodium lactate, sodium sulfate, sodium dihydrogen phosphate, disodium hydrogen phosphate, sodium acetate, sodium glycerophosphate, sodium carbonate, sodium amino acid salts, sodium propionate, sodium hydroxybutyrate, sodium gluconate, potassium chloride, potassium acetate, potassium gluconate, potassium bicarbonate, potassium glycerophosphate, potassium sulfate, potassium lactate, potassium iodide, potassium dihydrogen phosphate, dipotassium hydrogen phosphate, potassium citrate, potassium amino acid salts, potassium propionate, potassium hydroxybutyrate, calcium chloride, calcium gluconate, calcium lactate, calcium glycerophosphate, calcium pantothenate, calcium acetate, magnesium chloride, magnesium sulfate, magnesium glycerophosphate, magnesium acetate, magnesium lactate, amino acid magnesium salts, ammonium chloride, zinc sulfate, zinc chloride, zinc gluconate, zinc lactate, zinc acetate, ferrous sulfate, ferrous chloride, ferrous gluconate, copper sulfate, and manganese sulfate.

8. The method of any one of claims 1 to 7, wherein the nanoparticle composition is administered intravenously, intraarterially, intraosseously, or intracardially.

9. The nanoparticle composition has an oxygen content of 1 to 50,000 ml O ２ 9. The method of claim 1, wherein the nanoparticle composition is an oxygenated nanoparticle composition of 100 ml / 100 ml nanoparticle composition.

10. 10. The method of claim 1, wherein the nanoparticle composition has an emulsifier:lipophilic or hydrophobic component ratio (w / w) of about 1:200 to about 1:1.

7.

11. 11. The method of claim 1, wherein the nanoparticle composition comprises micelles and liposomes, and wherein the diameter of the micelles in the nanoparticle composition is in the range of 15 to 200 nm as measured by electron microscopy, and the diameter of the liposomes in the nanoparticle composition is in the range of 1 to 25 nm as measured by electron microscopy.

12. The method of any one of claims 1 to 11, wherein the magnesium ion concentration of the nanoparticle composition is below the physiological range.

13. 13. The method of any one of claims 1 to 12, wherein the nanoparticle composition further comprises one or more selected from the group consisting of a crystalloid agent, an oncotic agent, an anti-inflammatory agent, an immunomodulatory agent, and a lipid-soluble gas.

14. The method of any one of claims 1 to 13, wherein the nanoparticle composition further comprises glycerin.

15. 1. A method for treating a disease or condition associated with elevated procalcitonin in a subject, comprising: For subjects requiring treatment, an amphiphilic emulsifier in an amount of 0.1% to 100% (w / v); a fat-soluble or hydrophobic component in an amount of 0-35% (w / v); a polar liquid carrier; one or more electrolytes; administering an effective amount of a nanoparticle composition comprising: The method, wherein the nanoparticle composition comprises liposomes and / or micelles having diameters in the range of 1 to 800 nm.

16. 16. The method of claim 15, wherein the disease or condition associated with elevated procalcitonin is chronic or acute renal failure.

17. 16. The method of claim 15, wherein the disease or condition associated with elevated procalcitonin is chronic or acute liver failure.

18. 16. The method of claim 15, wherein the disease or condition associated with elevated procalcitonin is due to blood loss, sepsis, heart failure, or damage to the nervous system or status epilepticus.

19. 16. The method of claim 15, wherein the disease or condition associated with elevated procalcitonin is chronic or acute respiratory failure.

20. 16. The method of claim 15, wherein the disease or condition associated with elevated procalcitonin is age-related sarcopenia.

21. 16. The method of claim 15, wherein the disease or condition associated with elevated procalcitonin is dementia.

22. 16. The method of claim 15, wherein the disease or condition associated with elevated procalcitonin is orthopedic or non-orthopedic trauma.

23. 16. The method of claim 15, wherein the disease or condition associated with elevated procalcitonin is a surgical procedure.

24. 16. The method of claim 15, wherein the disease or condition associated with elevated procalcitonin is myocardial infarction.

25. 16. The method of claim 15, wherein the disease or condition associated with elevated procalcitonin is autism.

26. 16. The method of claim 15, wherein the disease or condition associated with elevated procalcitonin is ischemic stroke.

27. 16. The method of claim 15, wherein the disease or condition associated with elevated procalcitonin is Parkinson's disease.

28. 16. The method of claim 15, wherein the disease or condition associated with elevated procalcitonin is vasculitis.

29. 16. The method of claim 15, wherein the disease or condition associated with elevated procalcitonin is bone fracture.

30. 16. The method of claim 15, wherein the disease or condition associated with elevated procalcitonin is depression.

31. 16. The method of claim 15, wherein the disease or condition associated with elevated procalcitonin is cancer or cancer metastasis.

32. 1. A method for treating aging, comprising: For subjects requiring treatment, an amphiphilic emulsifier in an amount of 0.1% to 100% (w / v); a fat-soluble or hydrophobic component in an amount of 0-35% (w / v); a polar liquid carrier; one or more electrolytes; administering an effective amount of a nanoparticle composition comprising: The method, wherein the nanoparticle composition comprises liposomes and / or micelles having diameters in the range of 1 to 800 nm.

Images